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Sample records for dorsal hippocampus impairs

  1. Preferential loss of dorsal-hippocampus synapses underlies memory impairments provoked by short, multimodal stress

    PubMed Central

    Maras, P M; Molet, J; Chen, Y; Rice, C; Ji, S G; Solodkin, A; Baram, T Z

    2014-01-01

    The cognitive effects of stress are profound, yet it is unknown if the consequences of concurrent multiple stresses on learning and memory differ from those of a single stress of equal intensity and duration. We compared the effects on hippocampus-dependent memory of concurrent, hours-long light, loud noise, jostling and restraint (multimodal stress) with those of restraint or of loud noise alone. We then examined if differences in memory impairment following these two stress types might derive from their differential impact on hippocampal synapses, distinguishing dorsal and ventral hippocampus. Mice exposed to hours-long restraint or loud noise were modestly or minimally impaired in novel object recognition, whereas similar-duration multimodal stress provoked severe deficits. Differences in memory were not explained by differences in plasma corticosterone levels or numbers of Fos-labeled neurons in stress-sensitive hypothalamic neurons. However, although synapses in hippocampal CA3 were impacted by both restraint and multimodal stress, multimodal stress alone reduced synapse numbers severely in dorsal CA1, a region crucial for hippocampus-dependent memory. Ventral CA1 synapses were not significantly affected by either stress modality. Probing the basis of the preferential loss of dorsal synapses after multimodal stress, we found differential patterns of neuronal activation by the two stress types. Cross-correlation matrices, reflecting functional connectivity among activated regions, demonstrated that multimodal stress reduced hippocampal correlations with septum and thalamus and increased correlations with amygdala and BST. Thus, despite similar effects on plasma corticosterone and on hypothalamic stress-sensitive cells, multimodal and restraint stress differ in their activation of brain networks and in their impact on hippocampal synapses. Both of these processes might contribute to amplified memory impairments following short, multimodal stress. PMID:24589888

  2. Select Overexpression of Homer1a in Dorsal Hippocampus Impairs Spatial Working Memory

    PubMed Central

    Celikel, Tansu; Zivkovic, Aleksandar; Resnik, Evgeny; Hasan, Mazahir T.; Licznerski, Pawel; Osten, Pavel; Rozov, Andrej; Seeburg, Peter H.; Schwarz, Martin K.

    2007-01-01

    Long Homer proteins forge assemblies of signaling components involved in glutamate receptor signaling in postsynaptic excitatory neurons, including those underlying synaptic transmission and plasticity. The short immediate-early gene (IEG) Homer1a can dynamically uncouple these physical associations by functional competition with long Homer isoforms. To examine the consequences of Homer1a-mediated “uncoupling” for synaptic plasticity and behavior, we generated forebrain-specific tetracycline (tet) controlled expression of Venus-tagged Homer1a (H1aV) in mice. We report that sustained overexpression of H1aV impaired spatial working but not reference memory. Most notably, a similar impairment was observed when H1aV expression was restricted to the dorsal hippocampus (HP), which identifies this structure as the principal cortical area for spatial working memory. Interestingly, H1aV overexpression also abolished maintenance of CA3-CA1 long-term potentiation (LTP). These impairments, generated by sustained high Homer1a levels, identify a requirement for long Homer forms in synaptic plasticity and temporal encoding of spatial memory. PMID:18982121

  3. Impaired learning from errors in cannabis users: Dorsal anterior cingulate cortex and hippocampus hypoactivity.

    PubMed

    Carey, Susan E; Nestor, Liam; Jones, Jennifer; Garavan, Hugh; Hester, Robert

    2015-10-01

    The chronic use of cannabis has been associated with error processing dysfunction, in particular, hypoactivity in the dorsal anterior cingulate cortex (dACC) during the processing of cognitive errors. Given the role of such activity in influencing post-error adaptive behaviour, we hypothesised that chronic cannabis users would have significantly poorer learning from errors. Fifteen chronic cannabis users (four females, mean age=22.40 years, SD=4.29) and 15 control participants (two females, mean age=23.27 years, SD=3.67) were administered a paired associate learning task that enabled participants to learn from their errors, during fMRI data collection. Compared with controls, chronic cannabis users showed (i) a lower recall error-correction rate and (ii) hypoactivity in the dACC and left hippocampus during the processing of error-related feedback and re-encoding of the correct response. The difference in error-related dACC activation between cannabis users and healthy controls varied as a function of error type, with the control group showing a significantly greater difference between corrected and repeated errors than the cannabis group. The present results suggest that chronic cannabis users have poorer learning from errors, with the failure to adapt performance associated with hypoactivity in error-related dACC and hippocampal regions. The findings highlight a consequence of performance monitoring dysfunction in drug abuse and the potential consequence this cognitive impairment has for the symptom of failing to learn from negative feedback seen in cannabis and other forms of dependence. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  4. Redox dysregulation affects the ventral but not dorsal hippocampus: impairment of parvalbumin neurons, gamma oscillations, and related behaviors.

    PubMed

    Steullet, Pascal; Cabungcal, Jan-Harry; Kulak, Anita; Kraftsik, Rudolf; Chen, Ying; Dalton, Timothy P; Cuenod, Michel; Do, Kim Q

    2010-02-17

    Elevated oxidative stress and alteration in antioxidant systems, including glutathione (GSH) decrease, are observed in schizophrenia. Genetic and functional data indicate that impaired GSH synthesis represents a susceptibility factor for the disorder. Here, we show that a genetically compromised GSH synthesis affects the morphological and functional integrity of hippocampal parvalbumin-immunoreactive (PV-IR) interneurons, known to be affected in schizophrenia. A GSH deficit causes a selective decrease of PV-IR interneurons in CA3 and dendate gyrus (DG) of the ventral but not dorsal hippocampus and a concomitant reduction of beta/gamma oscillations. Impairment of PV-IR interneurons emerges at the end of adolescence/early adulthood as oxidative stress increases or cumulates selectively in CA3 and DG of the ventral hippocampus. Such redox dysregulation alters stress and emotion-related behaviors but leaves spatial abilities intact, indicating functional disruption of the ventral but not dorsal hippocampus. Thus, a GSH deficit affects PV-IR interneuron's integrity and neuronal synchrony in a region- and time-specific manner, leading to behavioral phenotypes related to psychiatric disorders.

  5. COGNITIVE IMPAIRMENT AND MORPHOLOGICAL CHANGES IN THE DORSAL HIPPOCAMPUS OF VERY OLD FEMALE RATS

    PubMed Central

    Morel, Gustavo R.; Andersen, Tomás; Pardo, Joaquín; Zuccolilli, Gustavo O.; Cambiaggi, Vanina L.; Hereñú, Claudia B.; Goya, Rodolfo G.

    2015-01-01

    The hippocampus, a medial temporal lobe structure necessary for the formation of spatial memory, is particularly affected by both normal and pathologic aging. In previous studies, we observed a significant age-related increase in dopaminergic neuron loss in the hypothalamus and the substantia nigra of female rats, which becomes more conspicuous at extreme ages. Here, we extend our studies by assessing spatial memory 4–6 months old (young), 26 months old (old) and 29–32 months old (senile) Sprague–Dawley female rats as well as the age-related histopathological changes in their dorsal hippocampus. Age changes in spatial memory performance were assessed with a modified version of the Barnes maze test. We employed two probe trials (PT), one and five days after training, respectively, in order to evaluate learning ability as well as short-term and longer-term spatial memory retention. A set of relevant hippocampal cell markers was also quantitated in the animals by means of an unbiased stereological approach. The results revealed that old rats perform better than senile rats in acquisition trials and young rats perform better than both aging groups. However, during short-term PT both aging groups showed a preserved spatial memory while in longer-term PT, spatial memory showed deterioration in both aged groups. Morphological analysis showed a marked decrease (94–97%) in doublecortin neuron number in the dentate gyrus in both aged groups and a reduction in glial fibrillary acidic protein-positive cell number in the stratum radiatum of aging rats. Astroglial process length and branching complexity decreased in the aged rats. We conclude that while target-seeking activity and learning ability decrease in aged females, spatial memory only declines in the longer-term tests. The reduction in neuroblast number and astroglial arborescence complexity in the dorsal hippocampus are likely to play a role in the cognitive deficits of aging rats. PMID:26141841

  6. Dopamine in the dorsal hippocampus impairs the late consolidation of cocaine-associated memory.

    PubMed

    Kramar, Cecilia P; Chefer, Vladimir I; Wise, Roy A; Medina, Jorge H; Barbano, M Flavia

    2014-06-01

    Cocaine is thought to be addictive because it elevates dopamine levels in the striatum, reinforcing drug-seeking habits. Cocaine also elevates dopamine levels in the hippocampus, a structure involved in contextual conditioning as well as in reward function. Hippocampal dopamine promotes the late phase of consolidation of an aversive step-down avoidance memory. Here, we examined the role of hippocampal dopamine function in the persistence of the conditioned increase in preference for a cocaine-associated compartment. Blocking dorsal hippocampal D1-type receptors (D1Rs) but not D2-type receptors (D2Rs) 12 h after a single training trial extended persistence of the normally short-lived memory; conversely, a general and a specific phospholipase C-coupled D1R agonist (but not a D2R or adenylyl cyclase-coupled D1R agonist) decreased the persistence of the normally long-lived memory established by three-trial training. These effects of D1 agents were opposite to those previously established in a step-down avoidance task, and were here also found to be opposite to those in a lithium chloride-conditioned avoidance task. After returning to normal following cocaine injection, dopamine levels in the dorsal hippocampus were found elevated again at the time when dopamine antagonists and agonists were effective: between 13 and 17 h after cocaine injection. These findings confirm that, long after the making of a cocaine-place association, hippocampal activity modulates memory consolidation for that association via a dopamine-dependent mechanism. They suggest a dynamic role for dorsal hippocampal dopamine in this late-phase memory consolidation and, unexpectedly, differential roles for late consolidation of memories for places that induce approach or withdrawal because of a drug association.

  7. Dopamine in the Dorsal Hippocampus Impairs the Late Consolidation of Cocaine-Associated Memory

    PubMed Central

    Kramar, Cecilia P; Chefer, Vladimir I; Wise, Roy A; Medina, Jorge H; Barbano, M Flavia

    2014-01-01

    Cocaine is thought to be addictive because it elevates dopamine levels in the striatum, reinforcing drug-seeking habits. Cocaine also elevates dopamine levels in the hippocampus, a structure involved in contextual conditioning as well as in reward function. Hippocampal dopamine promotes the late phase of consolidation of an aversive step-down avoidance memory. Here, we examined the role of hippocampal dopamine function in the persistence of the conditioned increase in preference for a cocaine-associated compartment. Blocking dorsal hippocampal D1-type receptors (D1Rs) but not D2-type receptors (D2Rs) 12 h after a single training trial extended persistence of the normally short-lived memory; conversely, a general and a specific phospholipase C-coupled D1R agonist (but not a D2R or adenylyl cyclase-coupled D1R agonist) decreased the persistence of the normally long-lived memory established by three-trial training. These effects of D1 agents were opposite to those previously established in a step-down avoidance task, and were here also found to be opposite to those in a lithium chloride-conditioned avoidance task. After returning to normal following cocaine injection, dopamine levels in the dorsal hippocampus were found elevated again at the time when dopamine antagonists and agonists were effective: between 13 and 17 h after cocaine injection. These findings confirm that, long after the making of a cocaine–place association, hippocampal activity modulates memory consolidation for that association via a dopamine-dependent mechanism. They suggest a dynamic role for dorsal hippocampal dopamine in this late-phase memory consolidation and, unexpectedly, differential roles for late consolidation of memories for places that induce approach or withdrawal because of a drug association. PMID:24442095

  8. Dorsal hippocampus inactivation impairs spontaneous recovery of Pavlovian magazine approach responding in rats.

    PubMed

    Campese, Vincent D; Delamater, Andrew R

    2014-08-01

    Destruction or inactivation of the dorsal hippocampus (DH) has been shown to eliminate the renewal of extinguished fear [1-4]. However, it has recently been reported that the contextual control of responding to extinguished appetitive stimuli is not disrupted when the DH is destroyed or inactivated prior to tests for renewal of Pavlovian conditioned magazine approach [5]. In the present study we extend the analysis of DH control of appetitive extinction learning to the spontaneous recovery of Pavlovian conditioned magazine approach responding. Subjects were trained to associate two separate stimuli with the delivery of food and had muscimol or vehicle infused into the DH prior to a single test-session for spontaneous recovery occurring immediately following extinction of one of these stimuli, but one week following extinction of the other. While vehicle treated subjects showed more recovery to the distally extinguished stimulus than the proximal one, muscimol treated subjects failed to show spontaneous recovery to either stimulus. This result suggests that, while the DH is not involved in the control of extinction by physical contexts [5], it may be involved when time is the gating factor controlling recovery of extinguished responding. Copyright © 2014 Elsevier B.V. All rights reserved.

  9. Dorsal hippocampus inactivation impairs spontaneous recovery of Pavlovian magazine approach responding in rats

    PubMed Central

    Campese, Vincent D.; Delamater, Andrew R.

    2014-01-01

    Destruction or inactivation of the dorsal hippocampus (DH) has been shown to eliminate the renewal of extinguished fear [1–4]. However, it has recently been reported that the contextual control of responding to extinguished appetitive stimuli is not disrupted when the DH is destroyed or inactivated prior to tests for renewal of Pavlovian conditioned magazine approach [5]. In the present study we extend the analysis of DH control of appetitive extinction learning to the spontaneous recovery of Pavlovian conditioned magazine approach responding. Subjects were trained to associate two separate stimuli with the delivery of food and had muscimol or vehicle infused into the DH prior to a single test-session for spontaneous recovery occurring immediately following extinction of one of these stimuli, but one week following extinction of the other. While vehicle treated subjects showed more recovery to the distally extinguished stimulus than the proximal one, muscimol treated subjects failed to show spontaneous recovery to either stimulus. This result suggests that, while the DH is not involved in the control of extinction by physical contexts [5], it may be involved when time is the gating factor controlling recovery of extinguished responding. PMID:24742862

  10. Nicotine improves ethanol-induced impairment of memory: possible involvement of nitric oxide in the dorsal hippocampus of mice.

    PubMed

    Raoufi, N; Piri, M; Moshfegh, A; Shahin, M-S

    2012-09-06

    In the present study, the possible involvement of nitric oxide (NO) systems in the dorsal hippocampus in nicotine's effect on ethanol-induced amnesia and ethanol state-dependent memory was investigated. Adult male mice were cannulated in the CA1 regions of the dorsal hippocampus and trained on a passive avoidance learning task for memory assessment. We found that pre-training intraperitoneal (i.p.) administration of ethanol (1 g/kg) decreased inhibitory avoidance memory when tested 24 h later. The response induced by pre-training ethanol was significantly reversed by pre-test administration of the drug. Similar to ethanol, pre-test administration of nicotine (0.4 and 0.8 μg/mouse, intra-CA1) alone and nicotine (0.2, 0.4 and 0.8 μg/mouse) plus an ineffective dose of ethanol also significantly reversed the amnesia induced by ethanol. Ethanol amnesia was also prevented by pre-test administration of L-arginine (1.2 μg/mouse, intra-CA1), a NO precursor. Interestingly, an ineffective dose of nicotine (0.2 μg/mouse) in combination with a low dose of L-arginine (0.8 μg/mouse) synergistically improved memory performance impaired by ethanol given before training. In contrast, pre-test intra-CA1 microinjection of L-NAME (NG-nitro-L-arginine methyl ester), a nitric oxide synthase (NOS) inhibitor (0.4 and 0.8 μg/mouse), which reduced memory retrieval in inhibitory avoidance task by itself, in combination with an effective dose of nicotine (0.4 μg/mouse) prevented the improving effect of nicotine on memory impaired by pre-training ethanol. Moreover, intra-CA1 microinjection of L-NAME reversed the L-arginine-induced potentiation of the nicotine response. The results suggest the importance of NO system(s) in the CA1 regions of the dorsal hippocampus for improving the effect of nicotine on the ethanol-induced amnesia.

  11. Ventral, but not dorsal, hippocampus inactivation impairs reward memory expression and retrieval in contexts defined by proximal cues.

    PubMed

    Riaz, Sadia; Schumacher, Anett; Sivagurunathan, Seyon; Van Der Meer, Matthijs; Ito, Rutsuko

    2017-07-01

    The hippocampus (HPC) has been widely implicated in the contextual control of appetitive and aversive conditioning. However, whole hippocampal lesions do not invariably impair all forms of contextual processing, as in the case of complex biconditional context discrimination, leading to contention over the exact nature of the contribution of the HPC in contextual processing. Moreover, the increasingly well-established functional dissociation between the dorsal (dHPC) and ventral (vHPC) subregions of the HPC has been largely overlooked in the existing literature on hippocampal-based contextual memory processing in appetitively motivated tasks. Thus, the present study sought to investigate the individual roles of the dHPC and the vHPC in contextual biconditional discrimination (CBD) performance and memory retrieval. To this end, we examined the effects of transient post-acquisition pharmacological inactivation (using a combination of GABAA and GABAB receptor agonists muscimol and baclofen) of functionally distinct subregions of the HPC (CA1/CA3 subfields of the dHPC and vHPC) on CBD memory retrieval. Additional behavioral assays including novelty preference, light-dark box and locomotor activity test were also performed to confirm that the respective sites of inactivation were functionally silent. We observed robust deficits in CBD performance and memory retrieval following inactivation of the vHPC, but not the dHPC. Our data provides novel insight into the differential roles of the ventral and dorsal HPC in reward contextual processing, under conditions in which the context is defined by proximal cues. © 2017 Wiley Periodicals, Inc.

  12. A high-fat diet impairs learning that is dependent on the dorsal hippocampus but spares other forms of learning.

    PubMed

    Stouffer, Eric M; Warninger, Elizabeth E; Michener, Paige N

    2015-12-01

    Two experiments were conducted to evaluate the effects of a high-fat diet (HFD) on two tasks that were either dependent on the dorsal hippocampus (DH) or independent of the DH. A total of 80 adult male Sprague Dawley rats were administered either a lard-based HFD (60% of calories from fat) or a control diet (10% of calories from fat) for 8 weeks, and then were trained and tested on either the latent cue preference (LCP) task or the conditioned cue preference (CCP) task in a 3-compartment box apparatus (2 end-compartments and 1 middle-compartment). The end compartments of the box apparatus contained either a single environmental cue (DH-independent) or multiple environmental cues (DH-dependent). During training trials for the LCP and CCP tasks, on alternating days, rats were given access to water in 1 of the 2 end compartments and no water in the opposite end compartment. Rats were water-replete during LCP training and were water-deprived during CCP training. During testing for both tasks, all rats were water-deprived and given free access to all compartments while the amounts of time spent in each compartment were recorded. Results showed that rats given the HFD demonstrated no compartment preferences during both LCP and CCP testing when the compartments contained multiple cues, while rats fed the control diet demonstrated normal compartment preference behavior. However, when the compartments contained a single environmental cue, rats given either the HFD and control diet demonstrated normal LCP and CCP learning. These results demonstrate that consumption of a HFD disrupted both LCP and CCP learning in a multiple-cue (DH-dependent) environment, but did not impair either type of learning in a single-cue (DH-independent) environment. This may be due to selective impairment of the DH caused by increased oxidative stress, inflammation, and/or disrupted neurotransmission produced by consumption of the HFD.

  13. Inactivation of the dorsal hippocampus or the medial prefrontal cortex impairs retrieval but has differential effect on spatial memory reconsolidation.

    PubMed

    Rossato, Janine I; Köhler, Cristiano A; Radiske, Andressa; Bevilaqua, Lia R M; Cammarota, Martín

    2015-11-01

    Active memories can incorporate new information through reconsolidation. However, the notion that memory retrieval is necessary for reconsolidation has been recently challenged. Non-reinforced retrieval induces hippocampus and medial prefrontal cortex (mPFC)-dependent reconsolidation of spatial memory in the Morris water maze (MWM). We found that the effect of protein synthesis inhibition on this process is abolished when retrieval of the learned spatial preference is hindered through mPFC inactivation but not when it is blocked by deactivation of dorsal CA1. Our results do not fully agree with the hypothesis that retrieval is unneeded for reconsolidation. Instead, they support the idea that a hierarchic interaction between the hippocampus and the mPFC controls spatial memory in the MWM, and indicate that this cortex is sufficient to retrieve the information essential to reconsolidate the spatial memory trace, even when the hippocampus is inactivated.

  14. Hippocampus and Pavlovian fear conditioning in rats: muscimol infusions into the ventral, but not dorsal, hippocampus impair the acquisition of conditional freezing to an auditory conditional stimulus.

    PubMed

    Maren, Stephen; Holt, William G

    2004-02-01

    The authors compared the effects of pharmacological inactivation of the dorsal hippocampus (DH) or ventral hippocampus (VH) on Pavlovian fear conditioning in rats. Freezing behavior served as the measure of fear. Pretraining infusions of muscimol, a GABAA receptor agonist, into the VH disrupted auditory, but not contextual, fear conditioning; DH infusions did not affect fear conditioning. Pretesting inactivation of the VH or DH did not affect the expression of conditional freezing. Pretraining electrolytic lesions of the VH reproduced the effects of muscimol infusions, whereas posttraining VH lesions disrupted both auditory and contextual freezing. Hence, neurons in the VH are importantly involved in the acquisition of auditory fear conditioning and the expression of auditory and contextual fear under some conditions.

  15. Reduction of Cav1.3 channels in dorsal hippocampus impairs the development of dentate gyrus newborn neurons and hippocampal-dependent memory tasks

    PubMed Central

    Kim, Su-Hyun; Park, Ye-Ryoung; Lee, Boyoung; Choi, Byungil; Kim, Hyun

    2017-01-01

    Cav1.3 has been suggested to mediate hippocampal neurogenesis of adult mice and contribute to hippocampal-dependent learning and memory processes. However, the mechanism of Cav1.3 contribution in these processes is unclear. Here, roles of Cav1.3 of mouse dorsal hippocampus during newborn cell development were examined. We find that knock-out (KO) of Cav1.3 resulted in the reduction of survival of newborn neurons at 28 days old after mitosis. The retroviral eGFP expression showed that both dendritic complexity and the number and length of mossy fiber bouton (MFB) filopodia of newborn neurons at ≥ 14 days old were significantly reduced in KO mice. Both contextual fear conditioning (CFC) and object-location recognition tasks were impaired in recent (1 day) memory test while passive avoidance task was impaired only in remote (≥ 20 days) memory in KO mice. Results using adeno-associated virus (AAV)-mediated Cav1.3 knock-down (KD) or retrovirus-mediated KD in dorsal hippocampal DG area showed that the recent memory of CFC was impaired in both KD mice but the remote memory was impaired only in AAV KD mice, suggesting that Cav1.3 of mature neurons play important roles in both recent and remote CFC memory while Cav1.3 in newborn neurons is selectively involved in the recent CFC memory process. Meanwhile, AAV KD of Cav1.3 in ventral hippocampal area has no effect on the recent CFC memory. In conclusion, the results suggest that Cav1.3 in newborn neurons of dorsal hippocampus is involved in the survival of newborn neurons while mediating developments of dendritic and axonal processes of newborn cells and plays a role in the memory process differentially depending on the stage of maturation and the type of learning task. PMID:28715454

  16. Binge ethanol exposure during adolescence leads to a persistent loss of neurogenesis in the dorsal and ventral hippocampus that is associated with impaired adult cognitive functioning

    PubMed Central

    Vetreno, Ryan P.; Crews, Fulton T.

    2015-01-01

    Adolescence is a developmental period that coincides with the maturation of adult cognitive faculties. Binge drinking is common during adolescence and can impact brain maturation. Using a rodent model of adolescent intermittent ethanol (AIE; 5.0 g/kg, i.g., 20% EtOH w/v; 2 days on/2 days off from postnatal day [P]25 to P55), we discovered that AIE treatment reduced neurogenesis (i.e., doublecortin-immunoreactive [DCX + IR] cells) in both the dorsal and ventral hippocampal dentate gyrus of late adolescent (P56) male Wistar rats that persisted during abstinence into adulthood (P220). This reduction in neurogenesis was accompanied by a concomitant reduction in proliferating cells (Ki-67) and an increase in cell death (cleaved caspase-3). In the hippocampus, AIE treatment induced a long-term upregulation of neuroimmune genes, including Toll-like receptor 4 (TLR4) and its endogenous agonist high-mobility group box 1 as well as several proinflammatory signaling molecules. Administration of lipopolysaccharide, a gram-negative endotoxin agonist at TLR4, to young adult rats (P70) produced a similar reduction of DCX + IR cells that was observed in AIE-treated animals. Behaviorally, AIE treatment impaired object recognition on the novel object recognition task when assessed from P163 to P165. Interestingly, object recognition memory was positively correlated with DCX + IR in both the dorsal and ventral hippocampal dentate gyrus while latency to enter the center of the apparatus was negatively correlated with DCX + IR in the ventral dentate gyrus. Together, these data reveal that adolescent binge ethanol exposure persistently inhibits neurogenesis throughout the hippocampus, possibly through neuroimmune mechanisms, which might contribute to altered adult cognitive and emotive function. PMID:25729346

  17. Infusion of lidocaine into the dorsal hippocampus before or after the shock training phase impaired conditioned freezing in a two-phase training task of contextual fear conditioning.

    PubMed

    Chang, Shih-Dar; Chen, Der-Yow; Liang, K C

    2008-02-01

    Learning in a contextual fear conditioning task involves forming a context representation and associating it with a shock. The dorsal hippocampus (DH) is implicated in representing the context, but whether it also has a role in associating the context and shock is unclear. To address this issue, male Wistar rats were trained on the task by a two-phase training paradigm, in which rats learned the context representation on day 1 and then reactivated it to associate with the shock on day 2; conditioned freezing was tested on day 3. Lidocaine was infused into the DH at various times in each of the two training sessions. Results showed that intra-DH infusion of lidocaine shortly before or after the context training session on day 1 impaired conditioned freezing, attesting to the DH involvement in context representation. Intra-DH infusion of lidocaine shortly before or after the shock training session on day 2 also impaired conditioned freezing. This deficit was reproduced by infusing lidocaine or APV (alpha-amino-5-phosphonovaleric acid) into the DH after activation of the context memory but before shock administration. The deficit was not due to drug-induced state-dependency, decreased shock sensitivity or reconsolidation failure of the contextual memory. These results suggest that in contextual fear conditioning integrity of the DH is required for memory processing of not only context representation but also context-shock association.

  18. Nicotine acts in the anterior cingulate, but not dorsal or ventral hippocampus, to reverse ethanol-induced learning impairments in the plus-maze discriminative avoidance task.

    PubMed

    Gulick, Danielle; Gould, Thomas J

    2011-01-01

    The current study examines the role of the dorsal and ventral hippocampus, and anterior cingulate in the interactive effects of ethanol and nicotine on learning, anxiety and locomotion in the plus-maze discriminative avoidance task, which allows dissociation of drug effects on each behaviour. At training, time spent in each of the arms of the elevated plus-maze was recorded for 5 minutes. Each time that the mouse entered the aversive enclosed arm, a light and white noise were turned on. At testing, no cues were turned on and time spent in each arm was recorded for 3 minutes. The effects of systemic ethanol (1.0 or 1.4 g/kg) and nicotine (0.35 µg/0.50 µl/side) infused into the anterior cingulate, dorsal and ventral hippocampus were examined, as were the interactive effects of systemic ethanol (1.0 g/kg) and nicotine (0.09 mg/kg) with the high-affinity nicotinic receptor antagonist dihydro-beta-erythroidine (DHβE) (18.0 µg/0.50 µl/side) infused into the anterior cingulate. Ethanol dose dependently decreased anxiety, increased locomotion, and decreased learning. Anterior cingulate-infused nicotine decreased anxiety and reversed ethanol-associated learning deficits. Anterior cingulate-infused DHβE blocked reversal of ethanol-induced learning deficits by systemic nicotine. Dorsal hippocampus-infused nicotine reversed ethanol-induced anxiolysis and hyper-locomotion (1.4 g/kg) but produced no behavioural changes in ethanol-naïve mice. Ventral hippocampus-infused nicotine enhanced anxiolysis associated with 1.4 g/kg ethanol, but had no other effects. The anterior cingulate is necessary and sufficient for nicotine reversal of ethanol-induced learning deficits. In addition, the anterior cingulate, dorsal hippocampus and ventral hippocampus may mediate drug-induced changes in anxiety.

  19. Influence of three-day morphine-treatment upon impairment of memory consolidation induced by cannabinoid infused into the dorsal hippocampus in rats.

    PubMed

    Zarrindast, Mohammad Reza; Navaeian, Majid; Nasehi, Mohammad

    2011-01-01

    In the present study, the effects of morphine treatment upon reduction of memory consolidation by post-training administration of the non-selective cannabinoid CB(1)/CB(2) receptor agonist, WIN55,212-2, into the dorsal hippocampus (intra-CA1) have been investigated in rats. Step-through inhibitory avoidance apparatus was used to test memory retrieval, which was made of two white and dark compartments. In training day, electric shocks were delivered to the grid floor of the dark compartment. On the test day, the animal was placed in the white compartment and allowed to enter the dark compartment. The latency with which the animal crossed into the dark compartment was recorded as memory retrieval. Morphine was injected subcutaneously (S.C.), once daily for three days, followed by a five day morphine-free period before training. Bilateral post-training intra-CA1 infusions of WIN55,212-2 (0.25 and 0.5 μg/rat) shortened the step-through latency, which suggested impaired memory consolidation. The deleterious effect of WIN55,212-2 (0.5 μg/rat) was prevented in rats previously injected with morphine (10 mg/kg/day × 3 days, S.C.). Prevention of the WIN55,212-2-induced amnesic-like effect was counteracted by the mu-receptor antagonist, naloxone, and the dopamine D(2) receptor antagonist, sulpiride, but not by the D(1) receptor antagonist, SCH 23390, when administered prior to each morphine injection. The results have suggested that subchronic morphine treatment may cause mu-opioid and D(2) receptor sensitization, which in turn prevents impairment of memory consolidation induced by WIN55,212-2.

  20. Are The Dorsal and Ventral Hippocampus functionally distinct structures?

    PubMed Central

    Fanselow, Michael S.; Dong, Hong-Wei

    2009-01-01

    One literature treats the hippocampus as a purely cognitive structure involved in memory; another treats it as a regulator of emotion whose dysfunction leads to psychopathology. We review behavioral, anatomical, and gene expression studies that together support a functional segmentation into 3 hippocampal compartments dorsal, intermediate and ventral. The dorsal hippocampus, which corresponds to the posterior hippocampus in primates, performs primarily cognitive functions. The ventral (anterior in primates) relates to stress, emotion and affect. Strikingly, gene expression in the dorsal hippocampus correlates with cortical regions involved in information processing, while genes expressed in the ventral hippocampus correlate with regions involved in emotion and stress (amygdala and hypothalamus). PMID:20152109

  1. Dorsal hippocampus is necessary for novel learning but sufficient for subsequent similar learning.

    PubMed

    Wang, Szu-Han; Finnie, Peter S B; Hardt, Oliver; Nader, Karim

    2012-11-01

    Our current understanding of brain mechanisms involved in learning and memory has been derived largely from studies using experimentally naïve animals. However, it is becoming increasingly clear that not all identified mechanisms may generalize to subsequent learning. For example, N-methyl-D-aspartate glutamate (NMDA) receptors in the dorsal hippocampus are required for contextual fear conditioning in naïve animals but not in animals previously trained in a similar task. Here we investigated how animals learn contextual fear conditioning for a second time-a response which is not due to habituation or generalization. We found that dorsal hippocampus infusions of voltage-dependent calcium channel blockers or the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) agonist impaired the first, not the second contextual learning. Only manipulations of the entire hippocampus led to an impairment in second learning. Specifically, inactivation of either the dorsal or ventral hippocampus caused the remaining portion of the hippocampus to acquire and consolidate the second learning. Thus, dorsal hippocampus seems necessary for initial contextual fear conditioning, but either the dorsal or ventral hippocampus is sufficient for subsequent conditioning in a different context. Together, these findings suggest that prior training experiences can change how the hippocampus processes subsequent similar learning.

  2. Unilateral lesion of dorsal hippocampus in adult rats impairs contralateral long-term potentiation in vivo and spatial memory in the early postoperative phase.

    PubMed

    Li, Hongjie; Wu, Xiaoyan; Bai, Yanrui; Huang, Yan; He, Wenting; Dong, Zhifang

    2012-05-01

    It is well documented that bilateral hippocampal lesions or unilateral hippocampal lesion at birth causes impairment of contralateral LTP and long-term memory. However, effects of unilateral hippocampal lesion in adults on contralateral in vivo LTP and memory are not clear. We here examined the influence of unilateral electrolytic dorsal hippocampal lesion in adult rats on contralateral LTP in vivo and spatial memory during different postoperative phases. We found that acute unilateral hippocampal lesion had no effect on contralateral LTP. However, contralateral LTP was impaired at 1 week after lesion, and was restored to the control level at postoperative week 4. Similarly, spatial memory was also impaired at postoperative week 1, and was restored at postoperative week 4. In addition, the rats at postoperative week 1 showed stronger spatial exploratory behavior in a novel open-field environment. The sham operation had no effects on contralateral LTP, spatial memory and exploration at either postoperative week 1 or week 4. These results suggest that unilateral dorsal hippocampal lesion in adult rats causes transient contralateral LTP impairment and spatial memory deficit. Copyright © 2012 Elsevier B.V. All rights reserved.

  3. Posttraining activation of CB1 cannabinoid receptors in the CA1 region of the dorsal hippocampus impairs object recognition long-term memory.

    PubMed

    Clarke, Julia R; Rossato, Janine I; Monteiro, Siomara; Bevilaqua, Lia R M; Izquierdo, Iván; Cammarota, Martín

    2008-09-01

    Evidence indicates that brain endocannabinoids are involved in memory processing. However, the participation of CB1 and CB2 cannabinoid receptors in recognition memory has not been yet conclusively determined. Therefore, we evaluated the effect of the posttraining activation of hippocampal cannabinoid receptors on the consolidation of object recognition memory. Rats with infusion cannulae stereotaxically aimed to the CA1 region of the dorsal hippocampus were trained in an object recognition learning task involving exposure to two different stimulus objects. Memory retention was assessed at different times after training. In the test sessions, one of the objects presented during training was replaced by a novel one. When infused in the CA1 region immediately after training, the non-selective cannabinoid receptor agonist WIN-55,212-2 and the endocannabinoid membrane transporter inhibitor VDM-11 blocked long-term memory retention in a dose-dependent manner without affecting short-term memory, exploratory behavior, anxiety state or the functionality of the hippocampus. The amnesic effect of WIN-55,212-2 and VDM-11 was not due to state-dependency and was completely reversed by co-infusion of the CB1 receptor antagonist AM-251 and mimicked by the CB1 receptor agonist ACEA but not by the CB2 receptor agonists JWH-015 and palmitoylethanolamide. Our data indicate that activation of hippocampal CB1 receptors early after training hampers consolidation of object recognition memory.

  4. Role of the Dorsal Hippocampus in Object Memory Load

    ERIC Educational Resources Information Center

    Sannino, Sara; Russo, Fabio; Torromino, Giulia; Pendolino, Valentina; Calabresi, Paolo; De Leonibus, Elvira

    2012-01-01

    The dorsal hippocampus is crucial for mammalian spatial memory, but its exact role in item memory is still hotly debated. Recent evidence in humans suggested that the hippocampus might be selectively involved in item short-term memory to deal with an increasing memory load. In this study, we sought to test this hypothesis. To this aim we developed…

  5. Role of the Dorsal Hippocampus in Object Memory Load

    ERIC Educational Resources Information Center

    Sannino, Sara; Russo, Fabio; Torromino, Giulia; Pendolino, Valentina; Calabresi, Paolo; De Leonibus, Elvira

    2012-01-01

    The dorsal hippocampus is crucial for mammalian spatial memory, but its exact role in item memory is still hotly debated. Recent evidence in humans suggested that the hippocampus might be selectively involved in item short-term memory to deal with an increasing memory load. In this study, we sought to test this hypothesis. To this aim we developed…

  6. Effects of dorsal hippocampus catecholamine depletion on paired-associates learning and place learning in rats.

    PubMed

    Roschlau, Corinna; Hauber, Wolfgang

    2017-04-14

    Growing evidence suggests that the catecholamine (CA) neurotransmitters dopamine and noradrenaline support hippocampus-mediated learning and memory. However, little is known to date about which forms of hippocampus-mediated spatial learning are modulated by CA signaling in the hippocampus. Therefore, in the current study we examined the effects of 6-hydroxydopamine-induced CA depletion in the dorsal hippocampus on two prominent forms of hippocampus-based spatial learning, that is learning of object-location associations (paired-associates learning) as well as learning and choosing actions based on a representation of the context (place learning). Results show that rats with CA depletion of the dorsal hippocampus were able to learn object-location associations in an automated touch screen paired-associates learning (PAL) task. One possibility to explain this negative result is that object-location learning as tested in the touchscreen PAL task seems to require relatively little hippocampal processing. Results further show that in rats with CA depletion of the dorsal hippocampus the use of a response strategy was facilitated in a T-maze spatial learning task. We suspect that impaired hippocampus CA signaling may attenuate hippocampus-based place learning and favor dorsolateral striatum-based response learning.

  7. Differential contribution of dorsal and ventral hippocampus to trace and delay fear conditioning.

    PubMed

    Esclassan, Frederic; Coutureau, Etienne; Di Scala, Georges; Marchand, Alain R

    2009-01-01

    Trace conditioning relies on the maintained representation of a stimulus across a trace interval, and may involve a persistent trace of the conditioned stimulus (CS) and/or a contribution of contextual conditioning. The role of hippocampal structures in these two types of conditioning was studied by means of pretraining lesions and reversible inactivation of the hippocampus in rats. Similar levels of conditioning to a tone CS and to the context were obtained with a trace interval of 30 s. Neurotoxic lesions of the whole hippocampus or reversible muscimol inactivation of the ventral hippocampus impaired both contextual and tone freezing in both trace- and delay-conditioned rats. Dorsal hippocampal injections impaired contextual freezing and trace conditioning, but not delay conditioning. No dissociation between trace and contextual conditioning was observed under any of these conditions. Altogether, these data indicate that the ventral and dorsal parts of the hippocampus compute different aspects of trace conditioning, with the ventral hippocampus being involved in fear and anxiety processes, and the dorsal hippocampus in the temporal and contextual aspects of event representation.

  8. Time-dependent involvement of the dorsal hippocampus in trace fear conditioning in mice.

    PubMed

    Misane, Ilga; Tovote, Philip; Meyer, Michael; Spiess, Joachim; Ogren, Sven Ove; Stiedl, Oliver

    2005-01-01

    Hippocampal and amygdaloid neuroplasticity are important substrates for Pavlovian fear conditioning. The hippocampus has been implicated in trace fear conditioning. However, a systematic investigation of the significance of the trace interval has not yet been performed. Therefore, this study analyzed the time-dependent involvement of N-methyl-D-aspartate (NMDA) receptors in the dorsal hippocampus in one-trial auditory trace fear conditioning in C57BL/6J mice. The NMDA receptor antagonist APV was injected bilaterally into the dorsal hippocampus 15 min before training. Mice were exposed to tone (conditioned stimulus [CS]) and footshock (unconditioned stimulus [US]) in the conditioning context without delay (0 s) or with CS-US (trace) intervals of 1-45 s. Conditioned auditory fear was determined 24 h after training by the assessment of freezing and computerized evaluation of inactivity in a new context; 2 h later, context-dependent memory was tested in the conditioning context. NMDA receptor blockade by APV markedly impaired conditioned auditory fear at trace intervals of 15 s and 30 s, but not at shorter trace intervals. A 45-s trace interval prevented the formation of conditioned tone-dependent fear. Context-dependent memory was always impaired by APV treatment independent of the trace interval. The results indicate that the dorsal hippocampus and its NMDA receptors play an important role in auditory trace fear conditioning at trace intervals of 15-30-s length. In contrast, NMDA receptors in the dorsal hippocampus are unequivocally involved in contextual fear conditioning independent of the trace interval. The results point at a time-dependent role of the dorsal hippocampus in encoding of noncontingent explicit stimuli. Preprocessing of long CS-US contingencies in the hippocampus appears to be important for the final information processing and execution of fear memories through amygdala circuits.

  9. Dorsal hippocampus contributes to model-based planning.

    PubMed

    Miller, Kevin J; Botvinick, Matthew M; Brody, Carlos D

    2017-09-01

    Planning can be defined as action selection that leverages an internal model of the outcomes likely to follow each possible action. Its neural mechanisms remain poorly understood. Here we adapt recent advances from human research for rats, presenting for the first time an animal task that produces many trials of planned behavior per session, making multitrial rodent experimental tools available to study planning. We use part of this toolkit to address a perennially controversial issue in planning: the role of the dorsal hippocampus. Although prospective hippocampal representations have been proposed to support planning, intact planning in animals with damaged hippocampi has been repeatedly observed. Combining formal algorithmic behavioral analysis with muscimol inactivation, we provide causal evidence directly linking dorsal hippocampus with planning behavior. Our results and methods open the door to new and more detailed investigations of the neural mechanisms of planning in the hippocampus and throughout the brain.

  10. Α2 GABAA receptor sub-units in the ventral hippocampus and α5 GABAA receptor sub-units in the dorsal hippocampus mediate anxiety and fear memory.

    PubMed

    McEown, K; Treit, D

    2013-11-12

    Temporary neuronal inactivation of the ventral hippocampus with the GABAA agonist muscimol suppresses unconditioned fear behavior (anxiety) but inactivation of the dorsal hippocampus does not. On the other hand, inactivating the dorsal hippocampus disrupts fear memory, while inactivating the ventral hippocampus does not. Here we investigate the roles of hippocampal GABAA receptor sub-units in mediating these anxiolytic and amnesic effects of GABAA receptor agonists. We microinfused TPA023 (α2 agonist) or TB-21007 (inverse α5 agonist) into the dorsal or ventral hippocampus prior to testing rats in two animal models of anxiety: the elevated plus-maze and shock-probe burying test. Twenty-four hours later rats were re-tested in the shock-probe chamber with a non-electrified probe to assess their memory of the initial shock-probe experience (i.e., fear memory). We found that TPA023 was anxiolytic in the plus-maze and shock-probe burying tests when microinfused into the ventral hippocampus. However, TPA023 did not affect anxiety-related behavior when infused into the dorsal hippocampus. Conversely, we found that the α5 sub-unit inverse agonist TB-21007 impaired rats' memory of the initial shock-probe experience when infused into the dorsal hippocampus, but not when infused into the ventral hippocampus. This double dissociation suggests that α2 GABAA receptor sub-units in the ventral hippocampus mediate unconditioned fear or anxiety, while α5 GABAA receptor sub-units in the dorsal hippocampus mediate conditioned fear memory. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

  11. Participation of the dorsal hippocampus in stimulus discrimination with scopolamine.

    PubMed

    Casasola, C; Mejía-Gervacio, S; Cruz-Pérez, M; Sánchez-Castillo, H; Velázquez-Martínez, D N

    2007-10-31

    Stimulus discrimination is the capacity of an organism to differentiate between stimuli and emit associated responses. The administration of the muscarinic antagonist scopolamine can be used as a stimulus by mammals in a discrimination task. The present study analyzes the contribution of the hippocampus in scopolamine discrimination and generalization. Male Wistar rats, weighing 250-300 g at the beginning of the experiment, were trained to discriminate between scopolamine (1.0 mg/kg, i.p.) and saline administration using a two-lever operant task; rats had to respond differentially to each lever depending on the preceding drug or saline administration. Once stimulus control was attained, rats were tested with different scopolamine doses (0.0, 0.056, 0.091, 0.16, 0.31 and 1.0 mg/kg, i.p.) in order to obtain generalization curves. After generalization the rats were randomly assigned to hippocampal CA1 lesion or control groups. Hippocampus impairment produced a transient decrease in the capacity to discriminate between scopolamine and saline conditions; nonetheless, scopolamine correct responses were rapidly recovered after a few sessions and even maintained after 90 days. Correct responses for saline condition were never recovered. The generalization curve obtained after hippocampus lesion showed a response gradient severely flattened. Results suggest that the hippocampus participates as a neural system supporting the sensitivity to detect discrete changes in stimulus properties and relational memory, more than on the capacity to recall for simple associative responses.

  12. Electrolytic lesions of the dorsal hippocampus disrupt renewal of conditional fear after extinction.

    PubMed

    Ji, Jinzhao; Maren, Stephen

    2005-01-01

    There is a growing body of evidence that the hippocampus is critical for context-dependent memory retrieval. In the present study, we used Pavlovian fear conditioning in rats to examine the role of the dorsal hippocampus (DH) in the context-specific expression of fear memory after extinction (i.e., renewal). Pre-training electrolytic lesions of the DH blunted the expression of conditional freezing to an auditory conditional stimulus (CS), but did not affect the acquisition of extinction to that CS. In contrast, DH lesions impaired the context-specific expression of extinction, eliminating the renewal of fear normally observed to a CS presented outside of the extinction context. Post-extinction DH lesions also eliminated the context dependence of fear extinction. These results are consistent with those using pharmacological inactivation of the DH and suggest that the DH is required for using contextual stimuli to regulate the expression of fear to a Pavlovian CS after extinction.

  13. Early-postnatal iron deficiency impacts plasticity in the dorsal and ventral hippocampus in piglets.

    PubMed

    Nelissen, Ellis; De Vry, Jochen; Antonides, Alexandra; Paes, Dean; Schepers, Melissa; van der Staay, Franz Josef; Prickaerts, Jos; Vanmierlo, Tim

    2017-03-19

    In this study, we investigated whether alterations in plasticity markers such as brain-derived neurotrophic factor (BDNF), p75 neurotrophin receptor (p75(NTR)) and tyrosine receptor kinase B (TrkB) are underlying iron deficiency (ID)-induced cognitive impairments in iron depleted piglets. Newborn piglets were either fed an iron-depleted diet (21mg Fe/kg) or an iron-sufficient diet (88mg Fe/kg) for four weeks. Subsequently, eight weeks after iron repletion (190-240mg Fe/kg) we found a significant decrease in mature BDNF (14kDa) and proBDNF (18kDa and 24kDa) protein levels in the ventral hippocampus, whereas we found increases in the dorsal hippocampus. The phosphorylation of cAMP response element binding protein (CREB) follows the mature BDNF protein level pattern. No effects were found on BDNF and CREB protein levels in the prefrontal cortex. The protein levels of the high affinity BDNF receptor, TrkB, was significantly decreased in both dorsal and ventral hippocampus of ID piglets, whereas it was increased in the prefrontal cortex. Together, our data suggest a disrupted hippocampal plasticity upon postnatal ID.

  14. Parvalbumin-positive GABAergic interneurons are increased in the dorsal hippocampus of the dystrophic mdx mouse.

    PubMed

    Del Tongo, Claudia; Carretta, Donatella; Fulgenzi, Gianluca; Catini, Claudio; Minciacchi, Diego

    2009-12-01

    Duchenne muscular dystrophy (DMD) is characterized by variable alterations of the dystrophin gene and by muscle weakness and cognitive impairment. We postulated an association between cognitive impairment and architectural changes of the hippocampal GABAergic system. We investigated a major subpopulation of GABAergic neurons, the parvalbumin-immunopositive (PV-I) cells, in the dorsal hippocampus of the mdx mouse, an acknowledged model of DMD. PV-I neurons were quantified and their distribution was compared in CA1, CA2, CA3, and dentate gyrus in wild-type and mdx mice. The cell morphology and topography of PV-I neurons were maintained. Conversely, the number of PV-I neurons was significantly increased in the mdx mouse. The percent increase of PV-I neurons was from 45% for CA2, up to 125% for the dentate gyrus. In addition, the increased parvalbumin content in the mdx hippocampus was confirmed by Western blot. A change in the hippocampus processing abilities is the expected functional counterpart of the modification displayed by PV-I GABAergic neurons. Altered hippocampal functionality can be responsible for part of the cognitive impairment in DMD.

  15. Dopamine release from the locus coeruleus to the dorsal hippocampus promotes spatial learning and memory

    PubMed Central

    Kempadoo, Kimberly A.; Mosharov, Eugene V.; Choi, Se Joon; Sulzer, David; Kandel, Eric R.

    2016-01-01

    Dopamine neurotransmission in the dorsal hippocampus is critical for a range of functions from spatial learning and synaptic plasticity to the deficits underlying psychiatric disorders such as attention-deficit hyperactivity disorder. The ventral tegmental area (VTA) is the presumed source of dopamine in the dorsal hippocampus. However, there is a surprising scarcity of VTA dopamine axons in the dorsal hippocampus despite the dense network of dopamine receptors. We have explored this apparent paradox using optogenetic, biochemical, and behavioral approaches and found that dopaminergic axons and subsequent dopamine release in the dorsal hippocampus originate from neurons of the locus coeruleus (LC). Photostimulation of LC axons produced an increase in dopamine release in the dorsal hippocampus as revealed by high-performance liquid chromatography. Furthermore, optogenetically induced release of dopamine from the LC into the dorsal hippocampus enhanced selective attention and spatial object recognition via the dopamine D1/D5 receptor. These results suggest that spatial learning and memory are energized by the release of dopamine in the dorsal hippocampus from noradrenergic neurons of the LC. The present findings are critical for identifying the neural circuits that enable proper attention selection and successful learning and memory. PMID:27930324

  16. Dopamine release from the locus coeruleus to the dorsal hippocampus promotes spatial learning and memory.

    PubMed

    Kempadoo, Kimberly A; Mosharov, Eugene V; Choi, Se Joon; Sulzer, David; Kandel, Eric R

    2016-12-20

    Dopamine neurotransmission in the dorsal hippocampus is critical for a range of functions from spatial learning and synaptic plasticity to the deficits underlying psychiatric disorders such as attention-deficit hyperactivity disorder. The ventral tegmental area (VTA) is the presumed source of dopamine in the dorsal hippocampus. However, there is a surprising scarcity of VTA dopamine axons in the dorsal hippocampus despite the dense network of dopamine receptors. We have explored this apparent paradox using optogenetic, biochemical, and behavioral approaches and found that dopaminergic axons and subsequent dopamine release in the dorsal hippocampus originate from neurons of the locus coeruleus (LC). Photostimulation of LC axons produced an increase in dopamine release in the dorsal hippocampus as revealed by high-performance liquid chromatography. Furthermore, optogenetically induced release of dopamine from the LC into the dorsal hippocampus enhanced selective attention and spatial object recognition via the dopamine D1/D5 receptor. These results suggest that spatial learning and memory are energized by the release of dopamine in the dorsal hippocampus from noradrenergic neurons of the LC. The present findings are critical for identifying the neural circuits that enable proper attention selection and successful learning and memory.

  17. Inactivation of the dorsal hippocampus does not affect learning during exploration of a novel environment.

    PubMed

    Gaskin, Stephane; Chai, Sin-Chee; White, Norman M

    2005-01-01

    The conditioned cue preference (CCP) task was used to study the ability of rats to discriminate between spatial locations. Food-deprived rats explored an eight-arm radial maze with no food present (pre-exposure). On subsequent days, they were alternately confined in one arm of the maze with food and in another arm with no food (training), followed by a preference test with no food present, to determine if they had learned to discriminate between the two arm locations. No injections were given during the two latter phases. With adjacent radial maze arms, rats given three 10-min pre-exposure sessions and four food-pairing trials exhibited a preference for their food-paired arms; rats not pre-exposed did not exhibit this preference. Rats pre-exposed 30 min after dorsal hippocampus injections of muscimol exhibited the preference. With widely separated maze arms, rats given two training trials with no pre-exposure exhibited a preference for the food-paired arm; rats that were given one pre-exposure session did not. Rats pre-exposed 30 min after dorsal hippocampus injections of muscimol did not exhibit the preference. The same intrahippocampal muscimol injections that failed to affect the influence of pre-exposure on CCP learning with both arm configurations impaired win-shift performance, a standard test of spatial learning. These findings suggest that a functional dorsal hippocampus is not required for the (incidental or latent) learning that occurs during unreinforced exploration of a novel environment. The information acquired during this activity subsequently produces a latent learning effect if it is used to discriminate between two ambiguous locations (adjacent arms) or a latent inhibition--like effect if it is used to discriminate between two unambiguous locations (separated maze arms). (c) 2005 Wiley-Liss, Inc.

  18. Nicotinic receptors in the dorsal and ventral hippocampus differentially modulate contextual fear conditioning.

    PubMed

    Kenney, Justin W; Raybuck, Jonathan D; Gould, Thomas J

    2012-08-01

    Nicotine administration alters various forms of hippocampus-dependent learning and memory. Increasing work has found that the dorsal and ventral hippocampus differentially contribute to multiple behaviors. Thus, the present study examined whether the effects of nicotine in the dorsal and ventral hippocampus have distinct influences on contextual fear learning in male C57BL/6J mice. Direct infusion of nicotine into the dorsal hippocampus resulted in an enhancement of contextual fear learning, whereas nicotine infused into the ventral hippocampus resulted in deficits. Nicotine infusions into the ventral hippocampus did not alter hippocampus-independent cued fear conditioning or time spent in the open arm of the elevated plus maze, a measure of anxiety, suggesting that the effects are due to alterations in contextual learning and not other general processes. Finally, results from using direct infusions of MLA, a low-affinity α7 nicotinic acetylcholine receptor (nAChR) antagonist, in conjunction with systemic nicotine, provide evidence that α7-nAChRs in the ventral hippocampus mediate the detrimental effect of ventral hippocampal nicotine on contextual fear learning. These results suggest that with systemic nicotine administration, competition exists between the dorsal and ventral hippocampus for behavioral control over contextual learning.

  19. Nicotinic Receptors in the Dorsal and Ventral Hippocampus Differentially Modulate Contextual Fear Conditioning

    PubMed Central

    Kenney, Justin W.; Raybuck, Jonathan D.; Gould, Thomas J.

    2012-01-01

    Nicotine administration alters various forms of hippocampus-dependent learning and memory. Increasing work has found that the dorsal and ventral hippocampus differentially contribute to multiple behaviors. Thus, the present study examined whether the effects of nicotine in the dorsal and ventral hippocampus have distinct influences on contextual fear learning in male C57BL/6J mice. Direct infusion of nicotine into the dorsal hippocampus resulted in an enhancement of contextual fear learning, whereas nicotine infused into the ventral hippocampus resulted in deficits. Nicotine infusions into the ventral hippocampus did not alter hippocampus-independent cued fear conditioning or time spent in the open arm of the elevated plus maze, a measure of anxiety, suggesting the effects are due to alterations in contextual learning and not other general processes. Finally, results from using direct infusions of MLA, a low-affinity α7 nicotinic acetylcholine receptor (nAChR) antagonist, in conjunction with systemic nicotine, provide evidence that α7-nAChRs in the ventral hippocampus mediate the detrimental effect of ventral hippocampal nicotine on contextual fear learning. These results suggest that with systemic nicotine administration, competition exists between the dorsal and ventral hippocampus for behavioral control over contextual learning. PMID:22271264

  20. Electrolytic Lesions of the Dorsal Hippocampus Disrupt Renewal of Conditional Fear after Extinction

    ERIC Educational Resources Information Center

    Ji, Jinzhao; Maren, Stephen

    2005-01-01

    There is a growing body of evidence that the hippocampus is critical for context-dependent memory retrieval. In the present study, we used Pavlovian fear conditioning in rats to examine the role of the dorsal hippocampus (DH) in the context-specific expression of fear memory after extinction (i.e., renewal). Pre-training electrolytic lesions of…

  1. Electrolytic Lesions of the Dorsal Hippocampus Disrupt Renewal of Conditional Fear after Extinction

    ERIC Educational Resources Information Center

    Ji, Jinzhao; Maren, Stephen

    2005-01-01

    There is a growing body of evidence that the hippocampus is critical for context-dependent memory retrieval. In the present study, we used Pavlovian fear conditioning in rats to examine the role of the dorsal hippocampus (DH) in the context-specific expression of fear memory after extinction (i.e., renewal). Pre-training electrolytic lesions of…

  2. Chronic Intermittent Hypoxia Induces Chronic Low-Grade Neuroinflammation in the Dorsal Hippocampus of Mice

    PubMed Central

    Sapin, Emilie; Peyron, Christelle; Roche, Frédéric; Gay, Nadine; Carcenac, Carole; Savasta, Marc; Levy, Patrick; Dematteis, Maurice

    2015-01-01

    Study Objectives: Obstructive sleep apnea (OSA) induces cognitive impairment that involves intermittent hypoxia (IH). Because OSA is recognized as a low-grade systemic inflammatory disease and only some patients develop cognitive deficits, we investigated whether IH-related brain consequences shared similar pathophysiology and required additional factors such as systemic inflammation to develop. Design: Nine-week-old male C57BL/6J mice were exposed to 1 day, 6 or 24 w of IH (alternating 21–5% FiO2 every 30 sec, 8 h/day) or normoxia. Microglial changes were assessed in the functionally distinct dorsal (dH) and ventral (vH) regions of the hippocampus using Iba1 immunolabeling. Then the study concerned dH, as vH only tended to be lately affected. Seven proinflammatory and anti-inflammatory cytokine messenger RNA (mRNA) were assessed at all time points using semiquantitative real-time reverse transcription polymerase chain reaction (RT-PCR). Similar mRNA analysis was performed after 6 w IH or normoxia associated for the past 3 w with repeated intraperitoneal low-dose lipopolysaccharide or saline. Measurements and Results: Chronic (6, 24 w) but not acute IH induced significant microglial changes in dH only, including increased density and morphological features of microglia priming. In dH, acute but not chronic IH increased IL-1β and RANTES/CCL5 mRNA, whereas the other cytokines remained unchanged. In contrast, chronic IH plus lipopolysaccharide increased interleukin (IL)-6 and IL10 mRNA whereas lipopolysaccharide alone did not affect these cytokines. Conclusion: The obstructive sleep apnea component intermittent hypoxia (IH) causes low-grade neuroinflammation in the dorsal hippocampus of mice, including early but transient cytokine elevations, delayed but long-term microglial changes, and cytokine response alterations to lipopolysaccharide inflammatory challenge. These changes may contribute to IH-induced cognitive impairment and pathological brain aging. Citation

  3. Ectopic sonic hedgehog signaling impairs telencephalic dorsal midline development: implication for human holoprosencephaly.

    PubMed

    Huang, Xi; Litingtung, Ying; Chiang, Chin

    2007-06-15

    Holoprosencephaly (HPE) is the most common developmental anomaly of the human forebrain, and in its severe form, the cerebral hemispheres fail to completely separate into two distinct halves. Although disruption of ventral forebrain induction is thought to underlie most HPE cases, a subset of HPE patients exhibits preferential dysgenesis of forebrain dorsal midline structures with unknown etiology. In this study, we show that Sonic hedgehog (Shh) lacking cholesterol moiety in one allele (ShhN/+) in mice can elicit ectopic Shh signaling in early telencephalon to induce ventral progenitor marker expression in the cortical region and impair telencephalic dorsal midline development. Prolonged ectopic ShhN signaling impaired Bmp and Wnt signaling from the dorsal patterning center through upregulation of Fgf8, leading to augmented cell proliferation, decreased cell death and impaired roof plate morphogenesis. Accordingly, ShhN/+ mutant telencephalic dorsal midline structures, including cortical hem, hippocampus and choroid plexus, either failed to form or were hypoplastic. Strikingly, ShhN/+ mutants displayed a spectrum of phenotypic features such as failure of anterior cerebral hemisphere to divide, hydrocephalus and cleft palate which have been observed in a human patient with milder HPE predicted to produce SHHN protein due to a truncation mutation in one SHH allele. We propose that elevated ectopic Shh signaling can impair dorsal telencephalic midline morphogenesis, and lead to non-cleavage of midline structures mimicking human HPE with dorsal midline defects.

  4. The effects of intra-dorsal hippocampus infusion of pregnenolone sulfate on memory function and hippocampal BDNF mRNA expression of biliary cirrhosis-induced memory impairment in rats.

    PubMed

    Dastgheib, M; Dehpour, A R; Heidari, M; Moezi, L

    2015-10-15

    Learning and memory impairment is one of the most challenging complications of cirrhosis and present treatments are unsatisfactory. The exact mechanism of cirrhosis cognitive dysfunction is unknown. Pregnenolone sulfate (PREGS) is an excitatory neurosteroid that acts as a N-methyl-D-aspartate (NMDA) receptor agonist and GABAA receptor antagonist. In this study we evaluated the effect of intra CA1 infusion of PREGS on cirrhotic rats' memory function using the Y-maze test. Hippocampal brain-derived neurotrophic factor (BDNF) mRNA expression was also evaluated. Three weeks after bile duct ligation (BDL) surgery, rats were under stereotaxic surgery for insertion of two guide cannulas in the CA1 region of the hippocampus. After 1-week of recovery, PREGS was administered through CA1 cannulas in cirrhotic rats, while control or sham groups received vehicle. For evaluation of NMDA receptor role in memory-enhancing effects of PREGS, DL-2-Amino-5-phosphonopentanoic acid (AP5) which is a potent and competitive antagonist of NMDA receptor, co-administered with PREGS and for assessment of hippocampal BDNF mRNA expression, quantitative Real-time reverse transcriptase-PCR (RT-PCR) was used. Results showed that 28 days after BDL, cirrhotic animals' memory significantly decreased in comparison with control and sham groups, while PREGS infusion could restore memory impairment (P<0.05). PREGS effects on memory of cirrhotic rats were antagonized by DAP5. RT-PCR findings have shown that hippocampal relative BDNF mRNA expression was up-regulated in PREGS-treated groups in comparison with the BDL group (P<0.001). Our findings suggest that PREGS has a memory-enhancing effect in cirrhosis memory deficit in acute therapy and this effect may be through NMDA (glutamate) receptor involvement and BDNF mRNA expression. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  5. Dorsal hippocampus involvement in trace fear conditioning with long, but not short, trace intervals in mice.

    PubMed

    Chowdhury, Najwa; Quinn, Jennifer J; Fanselow, Michael S

    2005-10-01

    Placing a "trace" interval between a warning signal and an aversive shock makes consolidation of the memory for trace conditioning hippocampus dependent. To determine the trace at which memory consolidation requires the hippocampus, mice were trained with 0-s, 1-s, 3-s, or 20-s trace intervals and tested for freezing to context and tone. Posttraining dorsal hippocampus (DH) lesions decreased context conditioning regardless of trace interval. However, DH lesions attenuated only the 20-s trace tone freezing. Like eyeblink conditioning, the DH is necessary for trace fear conditioning only at long trace intervals, but the time scale for the effective interval in fear conditioning is about 40 times longer. Manipulations that alter trace fear conditioning with short trace intervals probably do not reflect altered DH function. Given this difference in time scale along with the use of posttraining DH lesions, hippocampus dependency of trace conditioning is not related to a bridging function or response timing.

  6. Neurogenesis and precursor cell differences in the dorsal and ventral adult canine hippocampus.

    PubMed

    Lowe, Aileen; Dalton, Marshall; Sidhu, Kuldip; Sachdev, Perminder; Reynolds, Brent; Valenzuela, Michael

    2015-04-23

    During evolution a unique anterior-posterior flexure posited the canine dentate gyrus in two distinct dorsal and ventral positions. We therefore sought to explore neurogenesis and neurogenic cell-related difference along the canine hippocampal dorsal-ventral axis. Post mortem histological analysis revealed 49.1% greater doublecortin (DCX)-positive cells and a 158.5% greater percentage of double labeled DCX-positive/neuronal nuclei (NeuN) positive cells in the dorsal subgranular zone compared to the ventral. We then show neural precursor cells isolated from fresh hippocampal tissue are capable of proliferating long term, and after differentiation, express neuronal and glial markers. Dorsal hippocampal isolates produced a 120.0% higher frequency of sphere-forming neural precursor cells compared to ventral hippocampal tissue. Histological DCX and neurosphere assay results were highly correlated. Overall, we provide the first evidence that the dorsal canine hippocampus has a markedly higher rate of adult neurogenesis than the ventral hippocampus, possibly related to a greater frequency of contributory neural precursor cells.

  7. The involvement of dorsal hippocampus in dextromethorphan-induced state-dependent learning in mice.

    PubMed

    Zarrindast, Mohammad-Reza; Ownegh, Vahid; Rezayof, Ameneh; Ownegh, Farid

    2014-01-01

    In an effort to understand the effect of dextromethorphan (DM; 3-methoxy-17-methylmorphinan), a noncompetitive antagonist of the N-methyl-d-aspartate (NMDA) receptors on memory retrieval, male NMRI mice received intraperitoneal (i.p.) or intra-CA1 injection of this drug before or after training and before testing in passive avoidance task. Pre-training i.p. (20mg/kg) or intra-CA1 (0.5 and 1 μg/mouse) administration of DM induced amnesia in a dose-dependent manner. Post-training i.p. (10 and 20mg/kg) or intra-CA administration of DM (0.5 and 1 μg/mouse) however, did not affect the memory retrieval. Moreover, memory retrieval was impaired in animals receiving either i.p. (20mg/kg) or intra-CA1 administration of DM (0.5 and 1 μg/mouse) prior to testing, suggesting the DM-induced amnesia. Interestingly, the amnestic effect of pre-training i.p. (20mg/kg) or intra-CA1 administration of DM (1 μg/mouse) was restored in mice receiving pre-test i.p. (5 and 10mg/kg) or intra-CA1 (0.25 and 0.5 μg/mouse) administration of the drug, indicating DM-induced state-dependent learning. Taken together, it can be concluded that DM administration impairs memory retrieval in a dose- and time-dependent manner. Moreover, DM can induce state-dependent learning. Dorsal hippocampus appears to play an important role upon DM influence of learning and memory processes. Copyright © 2013 Elsevier Inc. All rights reserved.

  8. Phosphorylation of tyrosine receptor kinase B in the dorsal striatum and dorsal hippocampus is associated with response learning in a water plus maze.

    PubMed

    Pahng, Amanda R; Colombo, Paul J

    2017-02-01

    The dorsal hippocampus and dorsal striatum have dissociable roles in learning and memory that are related to region-specific changes in proteins necessary for neuronal plasticity and memory formation. There is additional evidence that the hippocampus and striatum can interact during memory formation. Phosphorylation of tyrosine receptor kinase B is important for memory formation in the hippocampus, but whether or not it has a role in striatum-dependent learning, or in interactions between the hippocampus and striatum, has not been examined. In the present study, we tested the hypothesis that response training increases pTrkB in the dorsal striatum, but decreases pTrkB in dorsal hippocampus, due to an interaction between the systems during memory formation. Results show a significant decrease in pTrkB levels in the dorsal hippocampus of rats trained on the response task compared with swim controls. Response training did not increase pTrkB levels in the dorsal striatum. Positive correlations were found between response learning and the total area of cells expressing pTrkB in the dorsal striatum, while no correlations were found in swim controls. Our results partially support our hypothesis and indicate that response learning is associated with a decrease in hippocampal pTrkB, while phosphorylation of TrkB in the dorsal striatum remains constant. This indicates that suppression of hippocampal pTrkB during response learning may be involved in striatum-dependent memory formation. Additionally, our findings suggest that activation of TrkB in a sparse arrangement of cells may be associated with faster acquisition of a response task. (PsycINFO Database Record

  9. Home-cage odors spatial cues elicit theta phase/gamma amplitude coupling between olfactory bulb and dorsal hippocampus.

    PubMed

    Pena, Roberta Ribas; Medeiros, Daniel de Castro; Guarnieri, Leonardo de Oliveira; Guerra, Julio Boriollo; Carvalho, Vinícius Rezende; Mendes, Eduardo Mazoni Andrade Marçal; Pereira, Grace Schenatto; Moraes, Márcio Flávio Dutra

    2017-09-07

    The brain oscillations may play a critical role in synchronizing neuronal assemblies in order to establish appropriate sensory-motor integration. In fact, studies have demonstrated phase-amplitude coupling of distinct oscillatory rhythms during cognitive processes. Here we investigated whether olfacto-hippocampal coupling occurs when mice are detecting familiar odors located in a spatially restricted area of a new context. The spatial olfactory task (SOT) was designed to expose mice to a new environment in which only one quadrant (target) contains odors provided by its own home-cage bedding. As predicted, mice showed a significant higher exploration preference to the target quadrant; which was impaired by olfactory epithelium lesion (ZnSO4). Furthermore, mice were able to discriminate odors from a different cage and avoided the quadrant with predator odor 2,4,5-trimethylthiazoline (TMT), reinforcing the specificity of the SOT. The local field potential (LFP) analysis of non-lesioned mice revealed higher gamma activity (35-100Hz) in the main olfactory bulb (MOB) and a significant theta phase/gamma amplitude coupling between MOB and dorsal hippocampus, only during exploration of home-cage odors (i.e. in the target quadrant). Our results suggest that exploration of familiar odors in a new context involves dynamic coupling between the olfactory bulb and dorsal hippocampus. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

  10. The effect of morphine sensitization on extracellular concentrations of GABA in dorsal hippocampus of male rats.

    PubMed

    Farahmandfar, Maryam; Zarrindast, Mohammad-Reza; Kadivar, Mehdi; Karimian, Seyed Morteza; Naghdi, Nasser

    2011-11-01

    Repeated, intermittent exposure to drugs of abuse, such as morphine results in response enhancements to subsequent drug treatments, a phenomenon referred to as behavioral sensitization. As persistent neuronal sensitization may contribute to the long-lasting consequences of drug abuse, characterizing the neurochemical mechanisms of sensitization is providing insights into addiction. Although it has been shown that GABAergic systems in the CA1 region of dorsal hippocampus are involved in morphine sensitization, the alteration of extracellular level of GABA in this area in morphine sensitization has not been investigated. In the present study, using the in vivo microdialysis technique, we investigated the effect of morphine sensitization on extracellular GABA concentration in CA1 region of dorsal hippocampus of freely moving rats. Sensitization was induced by subcutaneous (s.c.) injection of morphine, once daily for 3 days followed by 5 days free of the opioid treatment. The results showed that extracellular GABA concentration in CA1 was decreased following acute administration of morphine in non-sensitized rats. However, morphine-induced behavioral sensitization significantly increased the extracellular GABA concentration in this area. The enhancement of GABA in morphine sensitized rats was inhibited by administration of naloxone 30 min before each of three daily doses of morphine. These results suggest an adaptation of the GABAergic neuronal transmission in dorsal hippocampus induced by morphine sensitization and it is implied that opioid receptors may play an important role in this effect.

  11. Dorsal hippocampus: a site of action of neuropeptides on avoidance behavior?

    PubMed

    Greidanus, T B; De Wied, D

    1976-01-01

    Vasopressin and ACTH 4-10 induce a dose dependent long-term, respectively short-term inhibition of extinction of a pole jumping avoidance response in animals with sham lesions in the antero-dorsal hippocampus. Small lesions, causing a restricted damage in this area of the brain, partly inhibit the behavioral effect of vasopressin. Extensive lesions in the antero-dorsal hippocampus completely prevent the inhibitory effects of vasopressin and of ACTH 4-10 on extinction of the avoidance response. The extensive lesions in the dorsal hippocampus complex do not interfere with the rate of extinction, but acquisition of the response is retarded. These observations do not allow the conclusion that the hippocampal complex is the locus of action of neuropeptides in relation to avoidance behavior; it is more likely that this brain region is but one site of behavioral action of these hormones, and that the limbic system needs to be intact to permit the neuropeptides to exert their behavioral effects.

  12. Differential roles of the dorsal and ventral hippocampus in predator odor contextual fear conditioning.

    PubMed

    Wang, Melissa E; Fraize, Nicolas P; Yin, Linda; Yuan, Robin K; Petsagourakis, Despina; Wann, Ellen G; Muzzio, Isabel A

    2013-06-01

    The study of fear memory is important for understanding various anxiety disorders in which patients experience persistent recollections of traumatic events. These memories often involve associations of contextual cues with aversive events; consequently, Pavlovian classical conditioning is commonly used to study contextual fear learning. The use of predator odor as a fearful stimulus in contextual fear conditioning has become increasingly important as an animal model of anxiety disorders. Innate fear responses to predator odors are well characterized and reliable; however, attempts to use these odors as unconditioned stimuli in fear conditioning paradigms have proven inconsistent. Here we characterize a contextual fear conditioning paradigm using coyote urine as the unconditioned stimulus. We found that contextual conditioning induced by exposure to coyote urine produces long-term freezing, a stereotypic response to fear observed in mice. This paradigm is context-specific and parallels shock-induced contextual conditioning in that it is responsive to extinction training and manipulations of predator odor intensity. Region-specific lesions of the dorsal and ventral hippocampus indicate that both areas are independently required for the long-term expression of learned fear. These results in conjunction with c-fos immunostaining data suggest that while both the dorsal and ventral hippocampus are required for forming a contextual representation, the ventral region also modulates defensive behaviors associated with predators. This study provides information about the individual contributions of the dorsal and ventral hippocampus to ethologically relevant fear learning.

  13. Distinct effect of stress on 11beta-hydroxysteroid dehydrogenase type 1 and corticosteroid receptors in dorsal and ventral hippocampus.

    PubMed

    Ergang, P; Kuželová, A; Soták, M; Klusoňová, P; Makal, J; Pácha, J

    2014-01-01

    Multiple lines of evidence suggest the participation of the hippocampus in the feedback inhibition of the hypothalamus-pituitary-adrenal axis during stress response. This inhibition is mediated by glucocorticoid feedback due to the sensitivity of the hippocampus to these hormones. The sensitivity is determined by the expression of glucocorticoid (GR) and mineralocorticoid (MR) receptors and 11beta-hydroxysteroid dehydrogenase type 1 (11HSD1), an enzyme that regulates the conversion of glucocorticoids from inactive to active form. The goal of our study was to assess the effect of stress on the expression of 11HSD1, GR and MR in the ventral and dorsal region of the CA1 hippocampus in three different rat strains with diverse responses to stress: Fisher 344, Lewis and Wistar. Stress stimulated 11HSD1 in the ventral but not dorsal CA1 hippocampus of Fisher 344 but not Lewis or Wistar rats. In contrast, GR expression following stress was decreased in the dorsal but not ventral CA1 hippocampus of all three strains. MR expression was not changed in either the dorsal or ventral CA1 region. These results indicate that (1) depending on the strain, stress stimulates 11HSD1 in the ventral hippocampus, which is known to be involved in stress and emotion reactions whereas (2) independent of strain, stress inhibits GR in the dorsal hippocampus, which is predominantly involved in cognitive functions.

  14. Major neurotransmitter systems in dorsal hippocampus and basolateral amygdala control social recognition memory

    PubMed Central

    Garrido Zinn, Carolina; Clairis, Nicolas; Silva Cavalcante, Lorena Evelyn; Furini, Cristiane Regina Guerino; de Carvalho Myskiw, Jociane; Izquierdo, Ivan

    2016-01-01

    Social recognition memory (SRM) is crucial for reproduction, forming social groups, and species survival. Despite its importance, SRM is still relatively little studied. Here we examine the participation of the CA1 region of the dorsal hippocampus (CA1) and the basolateral amygdala (BLA) and that of dopaminergic, noradrenergic, and histaminergic systems in both structures in the consolidation of SRM. Male Wistar rats received intra-CA1 or intra-BLA infusions of different drugs immediately after the sample phase of a social discrimination task and 24-h later were subjected to a 5-min retention test. Animals treated with the protein synthesis inhibitor, anisomycin, into either the CA1 or BLA were unable to recognize the previously exposed juvenile (familiar) during the retention test. When infused into the CA1, the β-adrenoreceptor agonist, isoproterenol, the D1/D5 dopaminergic receptor antagonist, SCH23390, and the H2 histaminergic receptor antagonist, ranitidine, also hindered the recognition of the familiar juvenile 24-h later. The latter drug effects were more intense in the CA1 than in the BLA. When infused into the BLA, the β-adrenoreceptor antagonist, timolol, the D1/D5 dopamine receptor agonist, SKF38393, and the H2 histaminergic receptor agonist, ranitidine, also hindered recognition of the familiar juvenile 24-h later. In all cases, the impairment to recognize the familiar juvenile was abolished by the coinfusion of agonist plus antagonist. Clearly, both the CA1 and BLA, probably in that order, play major roles in the consolidation of SRM, but these roles are different in each structure vis-à-vis the involvement of the β-noradrenergic, D1/D5-dopaminergic, and H2-histaminergic receptors therein. PMID:27482097

  15. The role of NMDA receptors of the medial septum and dorsal hippocampus on memory acquisition.

    PubMed

    Khakpai, Fatemeh; Nasehi, Mohammad; Zarrindast, Mohammad-Reza

    2016-04-01

    The glutamatergic neurons in the medial septal/diagonal band of broca (MS/DB) affect the hippocampal functions by modulating the septo-hippocampal neurons. Our study investigated the possible role of NMDA receptors of the medial septum nucleus (MS) and dorsal hippocampus (CA1) on memory acquisition in male Wistar rats. Animals were bilaterally implanted with chronic cannulae in the MS and CA1. Rats were trained in a step-through type inhibitory avoidance task, and tested 24h after training to measure step-through latency as memory retrieval. Our results indicated that pre-training intra-MS or intra-CA1 infusions of NMDA (0.125 μg/rat) and D-AP7 (0.012 μg/rat) increased and decreased memory acquisition, respectively when compared to saline control group. Also, pre-training intra-CA1 and intra-MS injection of an effect dose of D-AP7 (0.012 μg/rat) along with an effect dose of NMDA (0.125 μg/rat) impaired memory acquisition. Interestingly, pre-training intra-CA1/MS infusion of D-AP7 (0.012 μg/rat) diminished memory response produced by pre-training injection of NMDA (0.125 μg/rat) in the MS/CA1, respectively (cross injection or bilateral injection). Also, all above doses of drugs did not alter locomotor activity. These results suggest that the glutamatergic pathway between the MS and CA1 regions is involved in memory acquisition process.

  16. Neurotoxic lesions of the dorsal hippocampus and Pavlovian fear conditioning in rats.

    PubMed

    Maren, S; Aharonov, G; Fanselow, M S

    1997-11-01

    Electrolytic lesions of the dorsal hippocampus (DH) produce deficits in both the acquisition and expression of conditional fear to contextual stimuli in rats. To assess whether damage to DH neurons is responsible for these deficits, we performed three experiments to examine the effects of neurotoxic N-methyl-D-aspartate (NMDA) lesions of the DH on the acquisition and expression of fear conditioning. Fear conditioning consisted of the delivery of signaled or unsignaled footshocks in a novel conditioning chamber and freezing served as the measure of conditional fear. In Experiment 1, posttraining DH lesions produced severe retrograde deficits in context fear when made either 1 or 28, but not 100, days following training. Pretraining DH lesions made 1 week before training did not affect contextual fear conditioning. Tone fear was impaired by DH lesions at all training-to-lesion intervals. In Experiment 2, posttraining (1 day), but not pretraining (1 week), DH lesions produced substantial deficits in context fear using an unsignaled shock procedure. In Experiment 3, pretraining electrolytic DH lesions produced modest deficits in context fear using the same signaled and unsignaled shock procedures used in Experiments 1 and 2, respectively. Electrolytic, but not neurotoxic, lesions also increased pre-shock locomotor activity. Collectively, this pattern of results reveals that neurons in the DH are not required for the acquisition of context fear, but have a critical and time-limited role in the expression of context fear. The normal acquisition and expression of context fear in rats with neurotoxic DH lesions made before training may be mediated by conditioning to unimodal cues in the context, a process that may rely less on the hippocampal memory system.

  17. Intact renewal after extinction of conditioned suppression with lesions of either the retrosplenial cortex or dorsal hippocampus.

    PubMed

    Todd, Travis P; Jiang, Matthew Y; DeAngeli, Nicole E; Bucci, David J

    2017-03-01

    Extinction of fear to a Pavlovian conditioned stimulus (CS) is known to be context-specific. When the CS is tested outside the context of extinction, fear returns, or renews. Several studies have demonstrated that renewal depends upon the hippocampus, although there are also studies where renewal was not impacted by hippocampal damage, suggesting that under some conditions context encoding and/or retrieval of extinction depends upon other regions. One candidate region is the retrosplenial cortex (RSC), which is known to contribute to contextual and spatial learning and memory. Using a conditioned-suppression paradigm, Experiment 1 tested the impact of pre-training RSC lesions on renewal of extinguished fear. Consistent with previous studies, lesions of the RSC did not impact acquisition or extinction of conditioned fear to the CS. Further, there was no evidence that RSC lesions impaired renewal, indicating that contextual encoding and/or retrieval of extinction does not depend upon the RSC. In Experiment 2, post-extinction lesions of either the RSC or dorsal hippocampus (DH) also had no impact on renewal. However, in Experiment 3, both RSC and DH lesions did impair performance in an object-in-place procedure, an index of place memory. RSC and DH contributions to extinction and renewal are discussed.

  18. Inhibition of local estrogen synthesis in the hippocampus impairs hippocampal memory consolidation in ovariectomized female mice

    PubMed Central

    Tuscher, Jennifer J.; Szinte, Julia S.; Starrett, Joseph R.; Krentzel, Amanda A.; Fortress, Ashley M.; Remage-Healey, Luke; Frick, Karyn M.

    2016-01-01

    The potent estrogen 17β-Estradiol (E2) plays a critical role in mediating hippocampal function, yet the precise mechanisms through which E2 enhances hippocampal memory remain unclear. In young adult female rodents, the beneficial effects of E2 on memory are generally attributed to ovarian-synthesized E2. However, E2 is also synthesized in the adult brain in numerous species, where it regulates synaptic plasticity and is synthesized in response to experiences such as exposure to females or conspecific song. Although de novo E2 synthesis has been demonstrated in rodent hippocampal cultures, little is known about the functional role of local E2 synthesis in mediating hippocampal memory function. Therefore, the present study examined the role of hippocampal E2 synthesis in hippocampal memory consolidation. Using bilateral dorsal hippocampal infusions of the aromatase inhibitor letrozole, we first found that blockade of dorsal hippocampal E2 synthesis impaired hippocampal memory consolidation. We next found that elevated levels of E2 in dorsal hippocampus observed 30 min after object training were blocked by dorsal hippocampal infusion of letrozole, suggesting that behavioral experience increases acute and local E2 synthesis. Finally, aromatase inhibition did not prevent exogenous E2 from enhancing hippocampal memory consolidation, indicating that hippocampal E2 synthesis is not necessary for exogenous E2 to enhance hippocampal memory. Combined, these data are consistent with the hypothesis that hippocampally-synthesized E2 is necessary for hippocampus-dependent memory consolidation in rodents. PMID:27178577

  19. The ventral hippocampus, but not the dorsal hippocampus is critical for learned approach-avoidance decision making.

    PubMed

    Schumacher, Anett; Vlassov, Ekaterina; Ito, Rutsuko

    2016-04-01

    The resolution of an approach-avoidance conflict induced by ambivalent information involves the appraisal of the incentive value of the outcomes and associated stimuli to orchestrate an appropriate behavioral response. Much research has been directed at delineating the neural circuitry underlying approach motivation and avoidance motivation separately. Very little research, however, has examined the neural substrates engaged at the point of decision making when opposing incentive motivations are experienced simultaneously. We hereby examine the role of the dorsal and ventral hippocampus (HPC) in a novel approach-avoidance decision making paradigm, revisiting a once popular theory of HPC function, which posited the HPC to be the driving force of a behavioral inhibition system that is activated in situations of imminent threat. Rats received pre-training excitotoxic lesions of the dorsal or ventral HPC, and were trained to associate different non-spatial cues with appetitive, aversive and neutral outcomes in three separate arms of the radial maze. On the final day of testing, a state of approach-avoidance conflict was induced by simultaneously presenting two cues of opposite valences, and comparing the time the rats spent interacting with the superimposed 'conflict' cue, and the neutral cue. The ventral HPC-lesioned group showed significant preference for the conflict cue over the neutral cue, compared to the dorsal HPC-lesioned, and control groups. Thus, we provide evidence that the ventral, but not dorsal HPC, is a crucial component of the neural circuitry concerned with exerting inhibitory control over approach tendencies under circumstances in which motivational conflict is experienced.

  20. Age-related differences in oligodendrogenesis across the dorsal-ventral axis of the mouse hippocampus.

    PubMed

    Yamada, Jun; Jinno, Shozo

    2014-08-01

    Oligodendrocyte precursor cells (OPCs) continue to divide and generate new oligodendrocytes (OLs) in the healthy adult brain. Although recent studies have indicated that adult oligodendrogenesis may be vital for the maintenance of normal brain function, the significance of adult oligodendrogenesis in brain aging remains unclear. In this study, we report a stereological estimation of age-related oligodendrogenesis changes in the mouse hippocampus: the dorsal subdivision is related to learning and memory, while the ventral subdivision is involved in emotional behaviors. To identify OPCs and OLs, we used a set of molecular markers, OL lineage transcription factor (Olig2) and platelet-derived growth factor receptor-alpha (PDGFαR). Intracellular dye injection shows that PDGFαR+/Olig2+ cells and PDGFαR-/Olig2+ cells can be defined as OPCs and OLs, respectively. In the dorsal Ammon's horn, the numbers of OPCs decreased with age, while those of OLs remained unchanged during aging. In the ventral Ammon's horn, the numbers of OPCs and OLs generally decreased with age. Bromodeoxyuridine (BrdU) fate-tracing analysis revealed that the numbers of BrdU+ mitotic OPCs in the Ammon's horn remained unchanged during aging in both the dorsal and ventral subdivisions. Unexpectedly, the numbers of BrdU+ newly generated OLs increased with age in the dorsal Ammon's horn, but remained unchanged in the ventral Ammon's horn. Together, the numbers of OLs in the dorsal Ammon's horn may be maintained during aging by increased survival of adult born OLs, while the numbers of OLs in the ventral Ammon's horn may be reduced with age due to the lack of such compensatory mechanisms. These observations provide new insight into the involvement of adult oligodendrogenesis in age-related changes in the structure and function of the hippocampus.

  1. Hippocampus and subregions of the dorsal striatum respond differently to a behavioral strategy change on a spatial navigation task

    PubMed Central

    Regier, Paul S.; Amemiya, Seiichiro

    2015-01-01

    Goal-directed and habit-based behaviors are driven by multiple but dissociable decision making systems involving several different brain areas, including the hippocampus and dorsal striatum. On repetitive tasks, behavior transitions from goal directed to habit based with experience. Hippocampus has been implicated in initial learning and dorsal striatum in automating behavior, but recent studies suggest that subregions within the dorsal striatum have distinct roles in mediating habit-based and goal-directed behavior. We compared neural activity in the CA1 region of hippocampus with anterior dorsolateral and posterior dorsomedial striatum in rats on a spatial choice task, in which subjects experienced reward delivery changes that forced them to adjust their behavioral strategy. Our results confirm the importance of the hippocampus in evaluating predictive steps during goal-directed behavior, while separate circuits in the basal ganglia integrated relevant information during automation of actions and recognized when new behaviors were needed to continue obtaining rewards. PMID:26084902

  2. Lasting Differential Effects on Plasticity Induced by Prenatal Stress in Dorsal and Ventral Hippocampus

    PubMed Central

    Grigoryan, Gayane; Segal, Menahem

    2016-01-01

    Early life adversaries have a profound impact on the developing brain structure and functions that persist long after the original traumatic experience has vanished. One of the extensively studied brain structures in relation to early life stress has been the hippocampus because of its unique association with cognitive processes of the brain. While the entire hippocampus shares the same intrinsic organization, it assumes different functions in its dorsal and ventral sectors (DH and VH, resp.), based on different connectivity with other brain structures. In the present review, we summarize the differences between DH and VH and discuss functional and structural effects of prenatal stress in the two sectors, with the realization that much is yet to be explored in understanding the opposite reactivity of the DH and VH to stressful stimulation. PMID:26881096

  3. Intrinsic excitability of CA1 pyramidal neurones from the rat dorsal and ventral hippocampus.

    PubMed

    Dougherty, Kelly A; Islam, Tasnim; Johnston, Daniel

    2012-11-15

    The hippocampus has a central role in learning and memory. Although once considered a relatively homogenous structure along the longitudinal axis, it has become clear that the rodent hippocampus can be anatomically and functionally divided into a dorsal component generally associated with spatial navigation, and a ventral component primarily associated with non-spatial functions that involve an emotional component. The ventral hippocampus (VHC) is also more sensitive to epileptogenic stimuli than the dorsal hippocampus (DHC), and seizures tend to originate in the VHC before spreading to other brain regions. Although synaptic and biochemical differences in DHC and VHC have been investigated, the intrinsic excitability of individual neurones from the DHC and VHC has received surprisingly little attention. In this study, we have characterized the intrinsic electrophysiological properties of CA1 pyramidal neurones from the DHC and the VHC using the whole-cell current-clamp method. Our results demonstrate that somatic current injections of equal magnitude elicit significantly more action potentials in VHC neurones than DHC neurones, and that this difference stems from the more depolarized resting membrane potential (RMP; 7 mV) and higher input resistance (R(in); 46 M measured from RMP) observed in VHC neurones. These differences in RMP and R(in) were also observed in dendritic whole-cell current-clamp recordings. Furthermore, morphological reconstructions of individual neurones revealed significant differences in the dendritic branching pattern between DHC and VHC neurones that could, in principle, contribute to the lower somatic R(in) of DHC neurones. Together, our results highlight significant differences in the intrinsic electrophysiological properties of CA1 pyramidal neurones across the longitudinal hippocampal axis, and suggest that VHC neurones are intrinsically more excitable than DHC neurones. This difference is likely to predispose the VHC to hyperexcitability.

  4. Intrinsic excitability of CA1 pyramidal neurones from the rat dorsal and ventral hippocampus

    PubMed Central

    Dougherty, Kelly A; Islam, Tasnim; Johnston, Daniel

    2012-01-01

    The hippocampus has a central role in learning and memory. Although once considered a relatively homogenous structure along the longitudinal axis, it has become clear that the rodent hippocampus can be anatomically and functionally divided into a dorsal component generally associated with spatial navigation, and a ventral component primarily associated with non-spatial functions that involve an emotional component. The ventral hippocampus (VHC) is also more sensitive to epileptogenic stimuli than the dorsal hippocampus (DHC), and seizures tend to originate in the VHC before spreading to other brain regions. Although synaptic and biochemical differences in DHC and VHC have been investigated, the intrinsic excitability of individual neurones from the DHC and VHC has received surprisingly little attention. In this study, we have characterized the intrinsic electrophysiological properties of CA1 pyramidal neurones from the DHC and the VHC using the whole-cell current-clamp method. Our results demonstrate that somatic current injections of equal magnitude elicit significantly more action potentials in VHC neurones than DHC neurones, and that this difference stems from the more depolarized resting membrane potential (RMP; Δ7 mV) and higher input resistance (Rin; Δ46 MΩ measured from RMP) observed in VHC neurones. These differences in RMP and Rin were also observed in dendritic whole-cell current-clamp recordings. Furthermore, morphological reconstructions of individual neurones revealed significant differences in the dendritic branching pattern between DHC and VHC neurones that could, in principle, contribute to the lower somatic Rin of DHC neurones. Together, our results highlight significant differences in the intrinsic electrophysiological properties of CA1 pyramidal neurones across the longitudinal hippocampal axis, and suggest that VHC neurones are intrinsically more excitable than DHC neurones. This difference is likely to predispose the VHC to hyperexcitability

  5. Hypothalamic and Other Connections with the Dorsal CA2 Area of the Mouse Hippocampus

    PubMed Central

    Cui, Zhenzhong; Gerfen, Charles R.; Young, W. Scott

    2013-01-01

    The CA2 area is an important, although relatively unexplored, component of the hippocampus. We used various tracers to provide a comprehensive analysis of CA2 connections in C57BL/6J mice. Using various adeno-associated viruses that express fluorescent proteins, we found a vasopressinergic projection from the paraventricular nuclei of the hypothalamus (PVN) to the CA2, as well as a projection from pyramidal neurons of the CA2 to the supramammillary nuclei. These projections were confirmed by retrograde tracing. As expected, we observed CA2 afferent projections from neurons in ipsilateral entorhinal cortical layer II as well as from bilateral dorsal CA2 and CA3 using retrograde tracers. Additionally, we saw CA2 neuronal input from bilateral medial septal nuclei, vertical and horizontal limbs of the nucleus of diagonal band of Broca, supramammillary nuclei (SUM) and median raphe nucleus. Dorsal CA2 injections of adeno-associated virus expressing green fluorescent protein revealed axonal projections primarily to dorsal CA1, CA2 and CA3 bilaterally. No projection was detected to the entorhinal cortex from the dorsal CA2. These results are consistent with recent observations that the dorsal CA2 forms disynaptic connections with the entorhinal cortex to influence dynamic memory processing. Mouse dorsal CA2 neurons send bilateral projections to the medial and lateral septal nuclei, vertical and horizontal limbs of the diagonal band of Broca and the SUM. Novel connections from the PVN and to the SUM suggest important regulatory roles for CA2 in mediating social and emotional input for memory processing. PMID:23172108

  6. Mechanical properties of the dorsal fin muscle of seahorse (Hippocampus) and pipefish (Syngnathus).

    PubMed

    Ashley-Ross, Miriam A

    2002-11-01

    The dorsal and pectoral fins are the primary locomotor organs in seahorses (Hippocampus) and pipefish (Syngnathus). The small dorsal fins beat at high oscillatory frequencies against the viscous medium of water. Both species are able to oscillate their fins at frequencies likely exceeding the point of flicker fusion for their predators, thus enhancing their ability to remain cryptic. High-speed video demonstrated that seahorse dorsal fins beat at 30-42 Hz, while pipefish dorsal fins oscillate at 13-26 Hz. In both species, the movement of the fin is a sinusoidal wave that travels down the fin from anterior to posterior. Mechanical properties of seahorse and pipefish dorsal fin muscles were tested in vitro by the work loop method. Maximum isometric stress was 176.1 kN/m(2) in seahorse and 111.5 kN/m(2) in pipefish. Work and power output were examined at a series of frequencies encompassing the range observed in vivo, and at a number of strains (percent length change during a contractile cycle) within each frequency. At a given strain, work per cycle declined with increasing frequency, while power output rose to a maximum at an intermediate frequency and then declined. Frequency and strain interacted in a complex fashion; optimal strain was inversely related to cycle frequency over most of the frequency range tested. Seahorse dorsal fin muscle was able to generate positive work at higher cycling frequencies than pipefish. Both species produced positive work at higher frequencies than have been reported for axial and fin muscles from other fish. Copyright 2002 Wiley-Liss, Inc.

  7. Cocaine- or stress-induced metaplasticity of LTP in the dorsal and ventral hippocampus.

    PubMed

    Keralapurath, Madhusudhanan M; Clark, Jason K; Hammond, Sherri; Wagner, John J

    2014-05-01

    Despite the well documented role of the hippocampus in various modes of drug reinstatement behavior, the persisting effects of in vivo cocaine exposure on hippocampal synaptic plasticity are not sufficiently understood. In this report we investigated the effects of cocaine conditioning on long-term potentiation (LTP) in the CA1 region of hippocampus along its septotemporal axis. Male Sprague-Dawley rats experienced a behavioral protocol, in which locomotor activity was monitored in response to various conditioning treatments. LTP was measured in ex vivo slice preparations taken 1-2 weeks after the last behavioral session from the ventral (vH) and dorsal (dH) sectors of hippocampus. Unexpectedly, experiencing the minor intermittent stimuli of the behavioral protocol caused stress-induced metaplastic changes in both vH (increased LTP) and dH (decreased LTP) in the saline conditioned rats relative to behaviorally naïve controls. These stress effects in the vH and dH were blocked by conditioning with either mineralocorticoid (spironolactone) or glucocorticoid (mifepristone) antagonists, respectively. Stress-induced metaplasticity in the vH was also prevented by prior administration of the kappa opioid antagonist nor-binaltorphimine. Cocaine conditioning induced locomotor sensitization and significantly increased LTP in the vH without causing significant change in LTP in the dH. Cocaine-induced metaplasticity in the vH was prevented by co-administration of the dopamine D2-like antagonist eticlopride during cocaine conditioning, but not by co-administration of the D1/5 antagonist SCH 23390. Our results suggest that the functional connectivity of hippocampus is altered by metaplastic triggers such as exposure to drugs of abuse and/or stressors, thereby shifting the efferent output of hippocampus from dH (cortical) toward vH (limbic) influenced circuits.

  8. Optogenetic fMRI reveals distinct, frequency-dependent networks recruited by dorsal and intermediate hippocampus stimulations

    PubMed Central

    Weitz, Andrew J.; Fang, Zhongnan; Lee, Hyun Joo; Fisher, Robert S.; Smith, Wesley C.; Choy, ManKin; Liu, Jia; Lin, Peter; Rosenberg, Matthew; Lee, Jin Hyung

    2014-01-01

    Although the connectivity of hippocampal circuits has been extensively studied, the way in which these connections give rise to large-scale dynamic network activity remains unknown. Here, we used optogenetic fMRI to visualize the brain network dynamics evoked by different frequencies of stimulation of two distinct neuronal populations within dorsal and intermediate hippocampus. Stimulation of excitatory cells in intermediate hippocampus caused widespread cortical and subcortical recruitment at high frequencies, whereas stimulation in dorsal hippocampus led to activity primarily restricted to hippocampus across all frequencies tested. Sustained hippocampal responses evoked during high-frequency stimulation of either location predicted seizure-like afterdischarges in video-EEG experiments, while the widespread activation evoked by high-frequency stimulation of intermediate hippocampus predicted behavioral seizures. A negative BOLD signal observed in dentate gyrus during dorsal, but not intermediate, hippocampus stimulation is proposed to underlie the mechanism for these differences. Collectively, our results provide insight into the dynamic function of hippocampal networks and their role in seizures. PMID:25462689

  9. Distinct behavioral consequences of short-term and prolonged GABAergic depletion in prefrontal cortex and dorsal hippocampus

    PubMed Central

    Reichel, Judith M.; Nissel, Sabine; Rogel-Salazar, Gabriela; Mederer, Anna; Käfer, Karola; Bedenk, Benedikt T.; Martens, Henrik; Anders, Rebecca; Grosche, Jens; Michalski, Dominik; Härtig, Wolfgang; Wotjak, Carsten T.

    2015-01-01

    GABAergic interneurons are essential for a functional equilibrium between excitatory and inhibitory impulses throughout the CNS. Disruption of this equilibrium can lead to various neurological or neuropsychiatric disorders such as epilepsy or schizophrenia. Schizophrenia itself is clinically defined by negative (e.g., depression) and positive (e.g., hallucinations) symptoms as well as cognitive dysfunction. GABAergic interneurons are proposed to play a central role in the etiology and progression of schizophrenia; however, the specific mechanisms and the time-line of symptom development as well as the distinct involvement of cortical and hippocampal GABAergic interneurons in the etiology of schizophrenia-related symptoms are still not conclusively resolved. Previous work demonstrated that GABAergic interneurons can be selectively depleted in adult mice by means of saporin-conjugated anti-vesicular GABA transporter antibodies (SAVAs) in vitro and in vivo. Given their involvement in schizophrenia-related disease etiology, we ablated GABAergic interneurons in the medial prefrontal cortex (mPFC) and dorsal hippocampus (dHPC) in adult male C57BL/6N mice. Subsequently we assessed alterations in anxiety, sensory processing, hyperactivity and cognition after long-term (>14 days) and short-term (<14 days) GABAergic depletion. Long-term GABAergic depletion in the mPFC resulted in a decrease in sensorimotor-gating and impairments in cognitive flexibility. Notably, the same treatment at the level of the dHPC completely abolished spatial learning capabilities. Short-term GABAergic depletion in the dHPC revealed a transient hyperactive phenotype as well as marked impairments regarding the acquisition of a spatial memory. In contrast, recall of a spatial memory was not affected by the same intervention. These findings emphasize the importance of functional local GABAergic networks for the encoding but not the recall of hippocampus-dependent spatial memories. PMID:25628548

  10. Distinct behavioral consequences of short-term and prolonged GABAergic depletion in prefrontal cortex and dorsal hippocampus.

    PubMed

    Reichel, Judith M; Nissel, Sabine; Rogel-Salazar, Gabriela; Mederer, Anna; Käfer, Karola; Bedenk, Benedikt T; Martens, Henrik; Anders, Rebecca; Grosche, Jens; Michalski, Dominik; Härtig, Wolfgang; Wotjak, Carsten T

    2014-01-01

    GABAergic interneurons are essential for a functional equilibrium between excitatory and inhibitory impulses throughout the CNS. Disruption of this equilibrium can lead to various neurological or neuropsychiatric disorders such as epilepsy or schizophrenia. Schizophrenia itself is clinically defined by negative (e.g., depression) and positive (e.g., hallucinations) symptoms as well as cognitive dysfunction. GABAergic interneurons are proposed to play a central role in the etiology and progression of schizophrenia; however, the specific mechanisms and the time-line of symptom development as well as the distinct involvement of cortical and hippocampal GABAergic interneurons in the etiology of schizophrenia-related symptoms are still not conclusively resolved. Previous work demonstrated that GABAergic interneurons can be selectively depleted in adult mice by means of saporin-conjugated anti-vesicular GABA transporter antibodies (SAVAs) in vitro and in vivo. Given their involvement in schizophrenia-related disease etiology, we ablated GABAergic interneurons in the medial prefrontal cortex (mPFC) and dorsal hippocampus (dHPC) in adult male C57BL/6N mice. Subsequently we assessed alterations in anxiety, sensory processing, hyperactivity and cognition after long-term (>14 days) and short-term (<14 days) GABAergic depletion. Long-term GABAergic depletion in the mPFC resulted in a decrease in sensorimotor-gating and impairments in cognitive flexibility. Notably, the same treatment at the level of the dHPC completely abolished spatial learning capabilities. Short-term GABAergic depletion in the dHPC revealed a transient hyperactive phenotype as well as marked impairments regarding the acquisition of a spatial memory. In contrast, recall of a spatial memory was not affected by the same intervention. These findings emphasize the importance of functional local GABAergic networks for the encoding but not the recall of hippocampus-dependent spatial memories.

  11. Chronic PARP-1 inhibition reduces carotid vessel remodeling and oxidative damage of the dorsal hippocampus in spontaneously hypertensive rats

    PubMed Central

    Eros, Krisztian; Magyar, Klara; Deres, Laszlo; Skazel, Arpad; Riba, Adam; Vamos, Zoltan; Kalai, Tamas; Gallyas, Ferenc; Sumegi, Balazs; Toth, Kalman

    2017-01-01

    Vascular remodeling during chronic hypertension may impair the supply of tissues with oxygen, glucose and other compounds, potentially unleashing deleterious effects. In this study, we used Spontaneously Hypertensive Rats and normotensive Wistar-Kyoto rats with or without pharmacological inhibition of poly(ADP-ribose)polymerase-1 by an experimental compound L-2286, to evaluate carotid artery remodeling and consequent damage of neuronal tissue during hypertension. We observed elevated oxidative stress and profound thickening of the vascular wall with fibrotic tissue accumulation induced by elevated blood pressure. 32 weeks of L-2286 treatment attenuated these processes by modulating mitogen activated protein kinase phosphatase-1 cellular levels in carotid arteries. In hypertensive animals, vascular inflammation and endothelial dysfunction was observed by NF-κB nuclear accumulation and impaired vasodilation to acetylcholine, respectively. Pharmacological poly(ADP-ribose)polymerase-1 inhibition interfered in these processes and mitigated Apoptosis Inducing Factor dependent cell death events, thus improved structural and functional alterations of carotid arteries, without affecting blood pressure. Chronic poly(ADP-ribose)polymerase-1 inhibition protected neuronal tissue against oxidative damage, assessed by nitrotyrosine, 4-hydroxinonenal and 8-oxoguanosine immunohistochemistry in the area of Cornu ammonis 1 of the dorsal hippocampus in hypertensive rats. In this area, extensive pyramidal cell loss was also attenuated by treatment with lowered poly(ADP-ribose)polymer formation. It also preserved the structure of fissural arteries and attenuated perivascular white matter lesions and reactive astrogliosis in hypertensive rats. These data support the premise in which chronic poly(ADP-ribose)polymerase-1 inhibition has beneficial effects on hypertension related tissue damage both in vascular tissue and in the hippocampus by altering signaling events, reducing oxidative

  12. Differential role of the dorsal hippocampus, ventro-intermediate hippocampus, and medial prefrontal cortex in updating the value of a spatial goal.

    PubMed

    De Saint Blanquat, Paul; Hok, Vincent; Save, Etienne; Poucet, Bruno; Chaillan, Franck A

    2013-05-01

    Encoding of a goal with a specific value while performing a place navigation task involves the medial prefrontal cortex (mPFC) and the dorsal hippocampus (dHPC), and depends on the coordination between mPFC and the ventro-intermediate hippocampus (vHPC).The present work investigates the contribution of mPFC, dHPC, and vHPC when the rat has to update the value of a goal. Rats were trained to navigate to an uncued goal in order to release a food pellet in a continuous place navigation task. When they had reached criterion performance level in the task, they were subjected to a single "flash session" in which they were exposed to an aversive strobe light during goal visits instead of receiving a food reward. Just before the flash session, the GABA(A) agonist muscimol was injected to temporarily inactivate mPFC, dHPC, or vHPC. The ability to recall the changed value of the goal was tested on the next day. We first demonstrate the aversive effect of the strobe light by showing that rats learn to avoid the goal much more rapidly in the flash session than during a simple extinction session in which goal visits are not rewarded. Furthermore, while dHPC inactivation had no effect on learning and recalling the new goal value, vHPC muscimol injections considerably delayed goal value updating during the flash session, which resulted in a slight deficit during recall. In contrast, mPFC muscimol injections induced faster goal value updating but the rats were markedly impaired on recalling the new goal value on the next day. These results suggest that, contrary to mPFC and dHPC, vHPC is required for updating the value of a goal. In contrast, mPFC is necessary for long-term retention of this updating.

  13. Inhibition of local estrogen synthesis in the hippocampus impairs hippocampal memory consolidation in ovariectomized female mice.

    PubMed

    Tuscher, Jennifer J; Szinte, Julia S; Starrett, Joseph R; Krentzel, Amanda A; Fortress, Ashley M; Remage-Healey, Luke; Frick, Karyn M

    2016-07-01

    The potent estrogen 17β-Estradiol (E2) plays a critical role in mediating hippocampal function, yet the precise mechanisms through which E2 enhances hippocampal memory remain unclear. In young adult female rodents, the beneficial effects of E2 on memory are generally attributed to ovarian-synthesized E2. However, E2 is also synthesized in the adult brain in numerous species, where it regulates synaptic plasticity and is synthesized in response to experiences such as exposure to females or conspecific song. Although de novo E2 synthesis has been demonstrated in rodent hippocampal cultures, little is known about the functional role of local E2 synthesis in mediating hippocampal memory function. Therefore, the present study examined the role of hippocampal E2 synthesis in hippocampal memory consolidation. Using bilateral dorsal hippocampal infusions of the aromatase inhibitor letrozole, we first found that blockade of dorsal hippocampal E2 synthesis impaired hippocampal memory consolidation. We next found that elevated levels of E2 in the dorsal hippocampus observed 30min after object training were blocked by dorsal hippocampal infusion of letrozole, suggesting that behavioral experience increases acute and local E2 synthesis. Finally, aromatase inhibition did not prevent exogenous E2 from enhancing hippocampal memory consolidation, indicating that hippocampal E2 synthesis is not necessary for exogenous E2 to enhance hippocampal memory. Combined, these data are consistent with the hypothesis that hippocampally-synthesized E2 is necessary for hippocampus-dependent memory consolidation in rodents. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Basic properties of somatosensory-evoked responses in the dorsal hippocampus of the rat

    PubMed Central

    Bellistri, Elisa; Aguilar, Juan; Brotons-Mas, Jorge R; Foffani, Guglielmo; de la Prida, Liset Menendez

    2013-01-01

    The hippocampus is a pivotal structure for episodic memory function. This ability relies on the possibility of integrating different features of sensory stimuli with the spatio-temporal context in which they occur. While recent studies now suggest that somatosensory information is already processed by the hippocampus, the basic mechanisms still remain unexplored. Here, we used electrical stimulation of the paws, the whisker pad or the medial lemniscus to probe the somatosensory pathway to the hippocampus in the anaesthetized rat, and multisite electrodes, in combination with tetrode and intracellular recordings, to look at the properties of somatosensory hippocampal responses. We found that peripheral and lemniscal stimulation elicited small local field potential responses in the dorsal hippocampus about 35–40 ms post-stimulus. Current source density analysis established the local nature of these responses, revealing associated synaptic sinks that were consistently confined to the molecular layer (ML) of the dentate gyrus (DG), with less regular activation of the CA1 stratum lacunosum moleculare (SLM). A delayed (40–45 ms), potentially active, current source that outlasted the SLM sink was present in about 50% cases around the CA1 pyramidal cell layer. Somatosensory stimulation resulted in multi-unit firing increases in the majority of DG responses (79%), whereas multi-unit firing suppression was observed in the majority of CA1 responses (62%). Tetrode and intracellular recordings of individual cells confirmed different firing modulation in the DG and the CA1 region, and verified the active nature of both the early ML sink and delayed somatic CA1 source. Hippocampal responses to somatosensory stimuli were dependent on fluctuations in the strength and composition of synaptic inputs due to changes of the ongoing local (hippocampal) and distant (cortical) state. We conclude that somatosensory signals reach the hippocampus mainly from layer II entorhinal cortex to

  15. Increasing CREB Function in the CA1 Region of Dorsal Hippocampus Rescues the Spatial Memory Deficits in a Mouse Model of Alzheimer's Disease

    PubMed Central

    Yiu, Adelaide P; Rashid, Asim J; Josselyn, Sheena A

    2011-01-01

    The principal defining feature of Alzheimer's disease (AD) is memory impairment. As the transcription factor CREB (cAMP/Ca2+ responsive element-binding protein) is critical for memory formation across species, we investigated the role of CREB in a mouse model of AD. We found that TgCRND8 mice exhibit a profound impairment in the ability to form a spatial memory, a process that critically relies on the dorsal hippocampus. Perhaps contributing to this memory deficit, we observed additional deficits in the dorsal hippocampus of TgCRND8 mice in terms of (1) biochemistry (decreased CREB activation in the CA1 region), (2) neuronal structure (decreased spine density and dendritic complexity of CA1 pyramidal neurons), and (3) neuronal network activity (decreased arc mRNA levels following behavioral training). Locally and acutely increasing CREB function in the CA1 region of dorsal hippocampus of TgCRND8 mice was sufficient to restore function in each of these key domains (biochemistry, neuronal structure, network activity, and most importantly, memory formation). The rescue produced by increasing CREB was specific both anatomically and behaviorally and independent of plaque load or Aβ levels. Interestingly, humans with AD show poor spatial memory/navigation and AD brains have disrupted (1) CREB activation, and (2) spine density and dendritic complexity in hippocampal CA1 pyramidal neurons. These parallel findings not only confirm that TgCRND8 mice accurately model key aspects of human AD, but furthermore, suggest the intriguing possibility that targeting CREB may be a useful therapeutic strategy in treating humans with AD. PMID:21734652

  16. Dexamethasone induces different morphological changes in the dorsal and ventral hippocampus of rats.

    PubMed

    Silva-Gómez, Adriana Berenice; Aguilar-Salgado, Yuritze; Reyes-Hernández, Diego Octavio; Flores, Gonzalo

    2013-01-01

    Dexamethasone (DEX), a synthetic glucocorticoid widely used in neurological illnesses because of its antiinflammatory properties, has many serious side effects, including severe psychiatric symptoms such as psychoses. The hippocampus is divided in the dorsal hippocampus (DH) and ventral hippocampus (VH) with each region having a subfield of CA1 and CA3 pyramidal layers. Great interest has recently emerged showing that the DH and VH are functionally different. In our work we determined whether, and what, changes occurred, after five days of DEX (0.2mg/kg) treatment, on the dendritic morphology of the CA1 and CA3 pyramidal neurons of the DH and VH of adult Sprague-Dawley rats. The dendritic morphology and characteristics were measured by using the Golgi-Cox procedure followed by a Sholl analysis. DEX decreased the number of dendritic spines of both apical and basolateral dendrites. Interestingly, this decrease was more pronounced in the VH. Only the VH neurons were affected by DEX with a decrease in their total dendritic length (TDL). An interesting point is that the VH neurons are longer that the DH neurons among the groups injected with saline only as the control. The length per branch order was only altered in the apical dendritic tree of the CA1 neurons. These data taken together show that the VH is more susceptible to DEX and its neurons are larger than the DH neurons. These results support previous observations related to differences between the DH and VH and suggest differences in the expression of the glucocorticoid receptors in connectivity and the space to elongate their dendritic arbor. Copyright © 2012 Elsevier B.V. All rights reserved.

  17. Dopamine D1/D5 receptors in the dorsal hippocampus are required for the acquisition and expression of a single trial cocaine-associated memory.

    PubMed

    Kramar, Cecilia P; Barbano, M Flavia; Medina, Jorge H

    2014-12-01

    The role of the hippocampus in memory supporting associative learning between contexts and unconditioned stimuli is well documented. Hippocampal dopamine neurotransmission modulates synaptic plasticity and memory processing of fear-motivated and spatial learning tasks. Much less is known about the involvement of the hippocampus and its D1/D5 dopamine receptors in the acquisition, consolidation and expression of memories for drug-associated experiences, more particularly, in the processing of single pairing cocaine conditioned place preference (CPP) training. To determine the temporal dynamics of cocaine CPP memory formation, we trained rats in a one-pairing CPP paradigm and tested them at different time intervals after conditioning. The cocaine-associated memory lasted 24 h but not 72 h. Then, we bilaterally infused the dorsal hippocampus with the GABA A receptor agonist muscimol or the D1/D5 dopamine receptor antagonist SCH 23390 at different stages to evaluate the mechanisms involved in the acquisition, consolidation or expression of cocaine CPP memory. Blockade of D1/D5 dopamine receptors at the moment of training impaired the acquisition of cocaine CPP memories, without having any effect when administered immediately or 12 h after training. The expression of cocaine CPP memory was also affected by the administration of SCH 23390 at the moment of the test. Conversely, muscimol impaired the consolidation of cocaine CPP memory only when administered 12 h post conditioning. These findings suggests that dopaminergic inputs to the dorsal hippocampus are required for the acquisition and expression of one trial cocaine-associated memory while neural activity of this structure is required for the late consolidation of these types of memories. Copyright © 2014 Elsevier Inc. All rights reserved.

  18. Intracellular mechanisms of cocaine-memory reconsolidation in the basolateral amygdala and dorsal hippocampus

    NASA Astrophysics Data System (ADS)

    Wells, Audrey Marie

    The ability of cocaine-associated environmental contexts to promote relapse in abstinent humans and reinstatement of cocaine-seeking behavior in laboratory animals depends on the formation and maintenance of maladaptive context-response-cocaine associative memories, the latter of which can be disrupted by manipulations that interfere with memory reconsolidation. Memory reconsolidation refers to a protein synthesis-dependent phenomenon whereby memory traces are reincorporated back into long-term memory storage following their retrieval and subsequent destabilization. To elucidate the distinctive roles of the basolateral amygdala (BLA) and dorsal hippocampus (DH) in the reconsolidation of context-response-cocaine memories, Experiments 1-3 evaluated novel molecular mechanisms within each structure that control this phenomenon. Experiment 1 tested the hypothesis that activation of the extracellular signal-regulated kinase (ERK) in the BLA and nucleus accumbens core (NACc - a substrate for Pavlovian cocaine-memory reconsolidation) would critically control instrumental cocaine-memory reconsolidation. To determine this, rats were re-exposed to a context that had previously been used for cocaine self-administration (i.e., cocaine memory-reactivation) and immediately thereafter received bilateral intra-BLA or intra-NACc microinfusions of the ERK inhibitor U0126 or vehicle (VEH) and were subsequently tested for drug context-induced cocaine-seeking behavior (non-reinforced lever responding) ~72 h later. Re-exposure to the cocaine-paired context at test fully reinstated cocaine-seeking behavior, relative to responding in an alternate, extinction context, and post-reactivation U0126 treatment in the BLA, but not the NACc, impaired cocaine-seeking behavior, relative to VEH. This effect was associated with a temporary increase in ERK2, but not ERK1, phosphorylation in the BLA and required explicit reactivation of the target memory trace (i.e., did not similarly manifest when U

  19. Dorsal hippocampus and medial prefrontal cortex each contribute to the retrieval of a recent spatial memory in rats.

    PubMed

    Cholvin, Thibault; Loureiro, Michaël; Cassel, Raphaelle; Cosquer, Brigitte; Herbeaux, Karin; de Vasconcelos, Anne Pereira; Cassel, Jean-Christophe

    2016-01-01

    Systems-level consolidation models propose that recent memories are initially hippocampus-dependent. When remote, they are partially or completely dependent upon the medial prefrontal cortex (mPFC). An implication of the mPFC in recent memory, however, is still debated. Different amounts of muscimol (MSCI 0, 30, 50, 80 and 250 ng in 1 µL PBS) were used to assess the impact of inactivation of the dorsal hippocampus (dHip) or the mPFC (targeting the prelimbic cortex) on a 24-h delayed retrieval of a platform location that rats had learned drug-free in a water maze. The two smallest amounts of MSCI (30 and 50 ng) did not affect recall, whatever the region. 80 ng MSCI infused into the dHip disrupted spatial memory retrieval, as did the larger amount. Infusion of MSCI into the mPFC did not alter performance in the 0-80 ng range. At 250 ng, it induced an as dramatic memory impairment as after efficient dHip inactivation. Stereological quantifications showed that 80 ng MSCI in the dHip and 250 ng MSCI in the mPFC induced a more than 80% reduction of c-Fos expression, suggesting that, beyond the amounts infused, it is the magnitude of the neuronal activity decrease which is determinant as to the functional outcome of the inactivation. Because, based on the literature, even 250 ng MSCI is a small amount, our results point to a contribution of the mPFC to the recall of a recently acquired spatial memory and thereby extend our knowledge about the functions of this major actor of cognition.

  20. Aerobic Exercise During Encoding Impairs Hippocampus-Dependent Memory.

    PubMed

    Soga, Keishi; Kamijo, Keita; Masaki, Hiroaki

    2017-10-06

    We investigated how aerobic exercise during encoding affects hippocampus-dependent memory through a source memory task that assessed hippocampus-independent familiarity and hippocampus-dependent recollection processes. Using a within-participants design, young adult participants performed a memory-encoding task while performing a cycling exercise or being seated. The subsequent retrieval phase was conducted while sitting on a chair. We assessed behavioral and event-related brain potential measures of familiarity and recollection processes during the retrieval phase. Results indicated that source accuracy was lower for encoding with exercise than for encoding in the resting condition. Event-related brain potential measures indicated that the parietal old/new effect, which has been linked to recollection processing, was observed in the exercise condition, whereas it was absent in the rest condition, which is indicative of exercise-induced hippocampal activation. These findings suggest that aerobic exercise during encoding impairs hippocampus-dependent memory, which may be attributed to inefficient source encoding during aerobic exercise.

  1. The expression of contextual fear conditioning involves activation of a NMDA receptor-nitric oxide-cGMP pathway in the dorsal hippocampus of rats.

    PubMed

    Fabri, Denise R S; Hott, Sara C; Reis, Daniel G; Biojone, Caroline; Corrêa, Fernando M A; Resstel, Leonardo B M

    2014-10-01

    The dorsal portion of the hippocampus is a limbic structure that is involved in fear conditioning modulation in rats. Moreover, evidence shows that the local dorsal hippocampus glutamatergic system, nitric oxide (NO) and cGMP modulate behavioral responses during aversive situations. Therefore, the present study investigated the involvement of dorsal hippocampus NMDA receptors and the NO/cGMP pathway in contextual fear conditioning expression. Male Wistar rats were submitted to an aversive contextual conditioning session and 48 h later they were re-exposed to the aversive context in which freezing, cardiovascular responses (increase of both arterial pressure and heart rate) and decrease of tail temperature were recorded. The intra-dorsal hippocampus administration of the NMDA receptor antagonist AP7, prior to the re-exposure to the aversive context, attenuated fear-conditioned responses. The re-exposure to the context evoked an increase in NO concentration in the dorsal hippocampus of conditioned animals. Similar to AP7 administration, we observed a reduction of contextual fear conditioning after dorsal hippocampus administration of either the neuronal NO synthase inhibitor N-propyl-L-arginine, the NO scavenger c-PTIO or the guanylate cyclase inhibitor ODQ. Therefore, the present findings suggest the possible existence of a dorsal hippocampus NMDA/NO/cGMP pathway modulating the expression of contextual fear conditioning in rats.

  2. HDAC I inhibition in the dorsal and ventral hippocampus differentially modulates predator-odor fear learning and generalization

    PubMed Central

    Yuan, Robin K.; Hebert, Jenna C.; Thomas, Arthur S.; Wann, Ellen G.; Muzzio, Isabel A.

    2015-01-01

    Although predator odors are ethologically relevant stimuli for rodents, the molecular pathways and contribution of some brain regions involved in predator odor conditioning remain elusive. Inhibition of histone deacetylases (HDACs) in the dorsal hippocampus has been shown to enhance shock-induced contextual fear learning, but it is unknown if HDACs have differential effects along the dorso-ventral hippocampal axis during predator odor fear learning. We injected MS-275, a class I HDAC inhibitor, bilaterally in the dorsal or ventral hippocampus of mice and found that it had no effects on innate anxiety in either region. We then assessed the effects of MS-275 at different stages of fear learning along the longitudinal hippocampal axis. Animals were injected with MS-275 or vehicle after context pre-exposure (pre-conditioning injections), when a representation of the context is first formed, or after exposure to coyote urine (post-conditioning injections), when the context becomes associated with predator odor. When MS-275 was administered after context pre-exposure, dorsally injected animals showed enhanced fear in the training context but were able to discriminate it from a neutral environment. Conversely, ventrally injected animals did not display enhanced learning in the training context but generalized the fear response to a neutral context. However, when MS-275 was administered after conditioning, there were no differences between the MS-275 and vehicle control groups in either the dorsal or ventral hippocampus. Surprisingly, all groups displayed generalization to a neutral context, suggesting that predator odor exposure followed by a mild stressor such as restraint leads to fear generalization. These results may elucidate distinct functions of the dorsal and ventral hippocampus in predator odor-induced fear conditioning as well as some of the molecular mechanisms underlying fear generalization. PMID:26441495

  3. Decoupling Actions from Consequences: Dorsal Hippocampal Lesions Facilitate Instrumental Performance, but Impair Behavioral Flexibility in Rats

    PubMed Central

    Busse, Sebastian; Schwarting, Rainer K. W.

    2016-01-01

    The present study is part of a series of experiments, where we analyze why and how damage of the rat’s dorsal hippocampus (dHC) can enhance performance in a sequential reaction time task (SRTT). In this task, sequences of distinct visual stimulus presentations are food-rewarded in a fixed-ratio-13-schedule. Our previous study (Busse and Schwarting, 2016) had shown that rats with lesions of the dHC show substantially shorter session times and post-reinforcement pauses (PRPs) than controls, which allows for more practice when daily training is kept constant. Since sequential behavior is based on instrumental performance, a sequential benefit might be secondary to that. In order to test this hypothesis in the present study, we performed two experiments, where pseudorandom rather than sequential stimulus presentation was used in rats with excitotoxic dorsal hippocampal lesions. Again, we found enhanced performance in the lesion-group in terms of shorter session times and PRPs. During the sessions we found that the lesion-group spent less time with non-instrumental behavior (i.e., grooming, sniffing, and rearing) after prolonged instrumental training. Also, such rats showed moderate evidence for an extinction impairment under devalued food reward conditions and significant deficits in a response-outcome (R-O)-discrimination task in comparison to a control-group. These findings suggest that facilitatory effects on instrumental performance after dorsal hippocampal lesions may be primarily a result of complex behavioral changes, i.e., reductions of behavioral flexibility and/or alterations in motivation, which then result in enhanced instrumental learning. PMID:27375453

  4. The entorhinal cortex, but not the dorsal hippocampus, is necessary for single-cue latent learning.

    PubMed

    Stouffer, Eric M

    2010-09-01

    Two experiments were conducted to examine the roles of the entorhinal cortex (EC), dorsal hippocampus (DH), and ventral hippocampus (VH) in a modified Latent Cue Preference (LCP) task. The modified LCP task utilized one visual cue in each compartment, compared to several multimodal cues used in a previous version. In the single-cue LCP task, water-replete rats drink water in one compartment of the LCP box on 1 day, and then have no water in a second compartment of the LCP box the following day (one training trial), for a total of three training trials. Rats are then water-deprived prior to a preference test, in which they are allowed to move freely between the two compartments with the water removed. Latent learning is demonstrated when water-deprived rats spend more time in the compartment that previously contained the water. Experiment 1 demonstrated that the single-cue LCP task results in the same irrelevant-incentive latent learning as the multicue LCP task. In addition, Experiment 1 replicated the finding that a compartment preference based on this latent learning requires a deprivation state during the preference test, while a compartment preference based on conditioning does not. Experiment 2 examined the effects of pretraining neurotoxin lesions of the EC, DH, and VH on this single-cue LCP task. Results showed that lesions of the EC and VH disrupted the irrelevant-incentive latent learning, while lesions of the DH did not. These results indicate that a latent learning task that involves one discrete compartment cue, rather than several compartmental cues, does not require the DH. Therefore, the EC appears to play a central role in single-cue latent learning in the LCP task.

  5. Effects of chronic malnourishment and aging on the ultrastructure of pyramidal cells of the dorsal hippocampus.

    PubMed

    Castro-Chavira, Susana Angelica; Aguilar-Vázquez, Azucena Ruth; Martínez-Chávez, Yvonne; Palma, Lourdes; Padilla-Gómez, Euridice; Diaz-Cintra, Sofia

    2016-10-01

    Malnourishment (M) produces permanent alterations during the development of the CNS and might modify the aging process. In pyramidal neurons (PN) of the hippocampus, which are associated with learning and memory performance, few studies have focused on changes at the subcellular level under chronic malnutrition (ChM) in young (Y, 2 months old) and aged (A, 22 months old) rats. The present work evaluated the extent to which ChM disrupts organelles in PN of the dorsal hippocampus CA1 as compared to controls (C). Ultrastructural analysis was performed at 8000×  and 20 000×  magnification: Nucleus eccentricity and somatic, cytoplasmic, and nuclear areas were measured; and in the PN perikaryon, density indices (number of organelles/cytoplasmic area) of Golgi membrane systems (GMS, normal, and swollen), mitochondria (normal and abnormal), and vacuolated organelles (lysosomes, lipofuscin granules, and multivesicular bodies (MVB)) were determined. The density of abnormal mitochondria, swollen GMS, and MVB increased significantly in the AChM group compared to the other groups. The amount of lipofuscin was significantly greater in the AChM than in the YChM groups - a sign of oxidative stress due to malnutrition and aging; however, in Y animals, ChM showed no effect on organelle density or the cytoplasmic area. An increased density of lysosomes as well as nucleus eccentricity was observed in the AC group, which also showed an increase in the cytoplasmic area. Malnutrition produces subcellular alterations in vulnerable hippocampal pyramidal cells, and these alterations may provide an explanation for the previously reported deficient performance of malnourished animals in a spatial memory task in which aging and malnutrition were shown to impede the maintenance of long-term memory.

  6. Cannabinoid CB1 receptor in dorsal telencephalic glutamatergic neurons: distinctive sufficiency for hippocampus-dependent and amygdala-dependent synaptic and behavioral functions.

    PubMed

    Ruehle, Sabine; Remmers, Floor; Romo-Parra, Hector; Massa, Federico; Wickert, Melanie; Wörtge, Simone; Häring, Martin; Kaiser, Nadine; Marsicano, Giovanni; Pape, Hans-Christian; Lutz, Beat

    2013-06-19

    A major goal in current neuroscience is to understand the causal links connecting protein functions, neural activity, and behavior. The cannabinoid CB1 receptor is expressed in different neuronal subpopulations, and is engaged in fine-tuning excitatory and inhibitory neurotransmission. Studies using conditional knock-out mice revealed necessary roles of CB1 receptor expressed in dorsal telencephalic glutamatergic neurons in synaptic plasticity and behavior, but whether this expression is also sufficient for brain functions is still to be determined. We applied a genetic strategy to reconstitute full wild-type CB1 receptor functions exclusively in dorsal telencephalic glutamatergic neurons and investigated endocannabinoid-dependent synaptic processes and behavior. Using this approach, we partly restored the phenotype of global CB1 receptor deletion in anxiety-like behaviors and fully restored hippocampus-dependent neuroprotection from chemically induced epileptiform seizures. These features coincided with a rescued hippocampal depolarization-induced suppression of excitation (DSE), a CB1 receptor-dependent form of synaptic plasticity at glutamatergic neurons. By comparison, the rescue of the CB1 receptor on dorsal telencephalic glutamatergic neurons prolonged the time course of DSE in the amygdala, and impaired fear extinction in auditory fear conditioning. These data reveal that CB1 receptor in dorsal telencephalic glutamatergic neurons plays a sufficient role to control neuronal functions that are in large part hippocampus-dependent, while it is insufficient for proper amygdala functions, suggesting an unexpectedly complex circuit regulation by endocannabinoid signaling in the amygdala. Our data pave the way to a better understanding of neuronal networks in the context of behavior, by fine-tuned interference with synaptic transmission processes.

  7. The small GTPase RhoA, but not Rac1, is essential for conditioned aversive memory formation through regulation of actin rearrangements in rat dorsal hippocampus.

    PubMed

    Wang, Jun; Wang, Yu-hua; Hou, Yuan-yuan; Xi, Tao; Liu, Yao; Liu, Jing-gen

    2013-06-01

    Actin rearrangements are induced in the dorsal hippocampus after conditioned morphine withdrawal, and involved in the formation of conditioned place aversion. In the present study, we investigated the mechanisms underlying the actin rearrangements in rat dorsal hippocampus induced by conditioned morphine withdrawal. The RhoA-ROCK pathway inhibitor Y27632 (8.56 μg/1 μL per side) or the Rac1 inhibitor NSC23766 (25 μg/1 μL per side) was microinjected into the dorsal hippocampus of rats. Conditioned place aversion (CPA) induced by naloxone-precipitated morphine withdrawal was assessed. Crude synaptosomal fraction of hippocampus was prepared, and the amount of F-actin and G-actin was measured with an Actin Polymerization Assay Kit. Conditioned morphine withdrawal significantly increased actin polymerization in the dorsal hippocampus at 1 h following the naloxone injection. Preconditioning with microinjection of Y27632, but not NSC23766, attenuated CPA, and blocked the increase in actin polymerization in the dorsal hippocampus. Our results suggest that the small GTPase RhoA, but not Rac1, in the dorsal hippocampus is responsible for CPA formation, mainly through its regulation of actin rearrangements.

  8. Dorsal hippocampus involvement in delay fear conditioning depends upon the strength of the tone-footshock association.

    PubMed

    Quinn, Jennifer J; Wied, Heather M; Ma, Quang D; Tinsley, Matthew R; Fanselow, Michael S

    2008-01-01

    The hippocampus is important for the formation of spatial, contextual, and episodic memories. For instance, lesions of the dorsal hippocampus (DH) produce demonstrable deficits in contextual fear conditioning. By contrast, it is generally agreed that the DH is not important for conditioning to a discrete cue (such as a tone or light) that is paired with footshock in a temporally contiguous fashion (delay conditioning). There are, however, some reports of hippocampus involvement in delay conditioning. The present series of experiments was designed to assess the conditions under which the hippocampus-dependent component of delay fear conditioning performance may be revealed. Here, we manipulated the number of conditioning trials and the intensity of the footshock in order to vary the strength of conditioning. The results indicate that the DH contributes to freezing performance to a delay conditioned tone when the conditioning parameters are relatively weak (few trials or low footshock intensity), but not when strong parameters are used. The results are discussed in terms of two parallel memory systems: a direct tone-footshock association that is independent of the hippocampus and a hippocampus-dependent memory for the conditioning session.

  9. Retroactive interference of object-in-context long-term memory: role of dorsal hippocampus and medial prefrontal cortex.

    PubMed

    Martínez, María Cecilia; Villar, María Eugenia; Ballarini, Fabricio; Viola, Haydée

    2014-12-01

    Retroactive interference (RI) is a type of amnesia in which a new learning experience can impair the expression of a previous one. It has been studied in several types of memories for over a century. Here, we aimed to study in the long-term memory (LTM) formation of an object-in-context task, defined as the recognition of a familiar object in a context different to that in which it was previously encountered. We trained rats with two sample trials, each taking place in a different context in association with different objects. Test sessions were performed 24 h later, to evaluate LTM for both object-context pairs using separate groups of trained rats. Furthermore, given the involvement of hippocampus (Hp) and medial prefrontal cortex (mPFC) in several recognition memories, we also analyzed the participation of these structures in the LTM formation of this task by the local infusion of muscimol. Our results show that object-in-context LTM formation is sensitive to RI by a different either familiar or novel object-context pair trial, experienced 1 h later. This interference occurs in a restricted temporal window and works on the LTM consolidation phase, leaving intact short-term memory expression. The second sample trial did not affect the object recognition part of the memory. Besides, muscimol treatment before the second sample trial blocks its object-in-context LTM and restores the first sample trial memory. We hypothesized that LTM-RI amnesia is probably caused by resources or cellular machinery competition in these brain regions when they are engaged in memory formation of the traces. In sum, when two different object-in-context memory traces are being processed, the second trace interferes with the consolidation of the first one requiring mPFC and CA1 dorsal Hp activation. © 2014 Wiley Periodicals, Inc.

  10. Protein synthesis in dorsal hippocampus supports the drug tolerance induced by prior elevated plus-maze experience.

    PubMed

    Gazarini, L; Stern, C A J; Bertoglio, L J

    2011-04-14

    Tolerance to the anxiolytic-like effect of drugs may develop because of a memory derived from prior experience in certain apparatuses such as the elevated plus-maze (EPM). Activity in basolateral amygdala was shown to be required for consolidating this knowledge. The dorsal hippocampus (DH) is also implicated in long-term memory consolidation, a process relying on new protein synthesis. It is unknown, however, whether the DH protein synthesis disruption would prevent the phenomenon rendering animals unresponsive to benzodiazepines in the EPM retest. To address this, we bilaterally infused the protein synthesis inhibitor anisomycin (ANI) into the rat DH 0, 3 or 6 h after, or 15 min before, the EPM test. DH infusion of ANI (80 μg) around the time of EPM testing preserved the anxiolysis of the midazolam (MDZ; 0.5 mg/kg, i.p.) in rats retested in the EPM 24 h later, suggesting that information consolidated by DH protein synthesis impacts on the subsequent animal's responsiveness to this drug. To examine whether impaired memory acquisition could also contribute to the prevention of MDZ tolerance seen in EPM-experienced animals infused with ANI before testing, the EPM retest was performed 3 h after testing to coincide with the temporal window in which short-term memory remains, for the reason that this process does not require protein synthesis for its formation. The pretest DH anisomycin infusion's ability to prevent the MDZ tolerance on retesting was now missing. This result confirms a specific action of the ANI on memory consolidation. We also found that rats express further avoidance to open-arms in the EPM retest. However, neither pretest nor posttest DH ANI infusion interfered with this pattern of results exhibited by EPM-experienced rats. Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

  11. Cannabidiol disrupts the consolidation of specific and generalized fear memories via dorsal hippocampus CB1 and CB2 receptors.

    PubMed

    Stern, Cristina A J; da Silva, Thiago R; Raymundi, Ana M; de Souza, Camila P; Hiroaki-Sato, Vinicius A; Kato, Luiza; Guimarães, Francisco S; Andreatini, Roberto; Takahashi, Reinaldo N; Bertoglio, Leandro J

    2017-10-01

    Pharmacological interventions able to modulate a fear memory while it is consolidated could have therapeutic value in tempering those maladaptively overconsolidated. Animal and human studies have shown the intensity of unconditioned stimulus delivered during fear conditioning influences qualitative and quantitative aspects of the memory to be established. By varying the shock intensity used for contextual pairing in rats, here we induced specific and more generalized long-term fear memories to investigate whether, how and where in the brain the cannabidiol (CBD; 3.0-30 mg/kg i.p.) could impair their consolidation and related outcomes. When given immediately after their acquisition, it reduced respectively the conditioned fear expression, and fear generalization, ultrasonic vocalizations at 22-kHz and the relative resistance to extinction. CBD had no effects on short-term fear memory, and its delayed treatment no longer affected the consolidation process. As the dorsal hippocampus (DH) modulates fear memory specificity and generalization, and cannabinoid type-1 (CB1) and type-2 (CB2) receptors contribute to consolidation, we investigated their involvement in CBD effects. Both systemic and intra-DH treatment with the CB1 receptor antagonist/inverse agonist AM251 or the CB2 receptor antagonist/inverse agonist AM630 prevented the disrupting CBD effects on consolidation. Since the CBD effects on the endocannabinoid transmission are probably indirect, we investigated and demonstrated the FAAH inhibitor URB597 induced effects similar to those of CBD when given systemically or intra-DH. Altogether, the present results suggest the CBD disrupts the consolidation of different fear memories via anandamide-mediated activation of DH CB1 and CB2 receptors. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. Different implications of the dorsal and ventral hippocampus on contextual memory retrieval after stress.

    PubMed

    Pierard, C; Dorey, R; Henkous, N; Mons, N; Béracochéa, D

    2017-09-01

    This study assessed the relative contributions of dorsal (dHPC) and ventral (vHPC) hippocampus regions in mediating the rapid effects of an acute stress on contextual memory retrieval. Indeed, we previously showed that an acute stress (3 electric footschocks; 0.9 mA each) delivered 15 min before the 24 h-test inversed the memory retrieval pattern in a contextual discrimination task. Specifically, mice learned in a four-hole board two successive discriminations (D1 and D2) varying by the color and texture of the floor. Twenty-four hours later, nonstressed animals remembered accurately D1 but not D2 whereas stressed mice showed an opposite memory retrieval pattern, D2 being more accurately remembered than D1. We showed here that, at the time of memory testing in that task, stressed animals exhibited no significant changes neither in pCREB activity nor in the time-course evolution of corticosterone into the vHPC; in contrast, a significant decrease in pCREB activity and a significant increase in corticosterone were observed in the dHPC as compared to nonstressed mice. Moreover, local infusion of the anesthetic lidocaine into the vHPC 15 min before the onset of the stressor did not modify the memory retrieval pattern in nonstress and stress conditions whereas lidocaine infusion into the dHPC induced in nonstressed mice an memory retrieval pattern similar to that observed in stressed animals. The overall set of data shows that memory retrieval in nonstress condition involved primarily the dHPC and that the inversion of memory retrieval pattern after stress is linked to a dHPC but not vHPC dysfunction. © 2017 Wiley Periodicals, Inc.

  13. Repeated administration of dopaminergic agents in the dorsal hippocampus and morphine-induced place preference.

    PubMed

    Zarrindast, M-R; Nasehi, M; Rostami, P; Rezayof, A; Fazli-Tabaei, S

    2005-03-01

    The aim of the present experiments was to investigate whether repeated intra-hippocampal CA1 (intra-CA1) administration of dopaminergic agents can affect morphine-induced conditioned place preference (CPP). Effects of repeated intra-CA1 injections of dopamine (DA) receptor agonists and antagonists on morphine-induced CPP in rats were investigated using an unbiased 3-day schedule of place conditioning. Animals receiving once-daily subcutaneous (s.c.) injections of morphine (1-9 mg/kg) or saline (1.0 ml/kg, s.c.) showed a significant place preference in a dose-dependent manner: the maximum response was observed with 3 mg/kg morphine. Three days' intra-CA1 injections of apomorphine (0.25-1 microg/rat) followed by 5 days free of the drug, significantly decreased morphine CPP (1 and 3 mg/kg, s.c.). Moreover, pre-treatment with the highest dose of apomorphine (1 microg/rat) altered the effect of morphine to an aversive response. The morphine (1 and 3 mg/kg) CPP was also significantly decreased in animals that previously received three intra-CA1 injections of SKF 38393 (2-9 microg/rat), quinpirole (1-3 microg/rat) or sulpiride (1-3 microg/rat), and significantly increased in animals that had previously received three intra-CA1 injections of SCH 23390 (0.02 microg/rat). The 3-day pre-treatment with apomorphine, SKF 38393 or quinpirole reduced locomotor activity in the test session, while SCH 23390 and sulpiride did not have any influence on locomotor activity. It is concluded that repeated injections of DA receptor agents in the dorsal hippocampus, followed by 5 days free of the drugs, can affect morphine reward.

  14. Neurotoxic kynurenine metabolism is increased in the dorsal hippocampus and drives distinct depressive behaviors during inflammation

    PubMed Central

    Parrott, J M; Redus, L; Santana-Coelho, D; Morales, J; Gao, X; O'Connor, J C

    2016-01-01

    The kynurenine pathway of tryptophan metabolism has an important role in mediating the behavioral effects of inflammation, which has implications in understanding neuropsychiatric comorbidity and for the development of novel therapies. Inhibition of the rate-limiting enzyme, indoleamine 2,3-dioxygenase (IDO), prevents the development of many of these inflammation-induced preclinical behaviors. However, dysregulation in the balance of downstream metabolism, where neuroactive kynurenines are generated, is hypothesized to be a functionally important pathogenic feature of inflammation-induced depression. Here we utilized two novel transgenic mouse strains to directly test the hypothesis that neurotoxic kynurenine metabolism causes depressive-like behavior following peripheral immune activation. Wild-type (WT) or kynurenine 3-monooxygenase (KMO)-deficient (KMO−/−) mice were administered either lipopolysaccharide (LPS, 0.5 mg kg−1) or saline intraperitoneally. Depressive-like behavior was measured across multiple domains 24 h after immune challenge. LPS precipitated a robust depressive-like phenotype, but KMO−/− mice were specifically protected from LPS-induced immobility in the tail suspension test (TST) and reduced spontaneous alternations in the Y-maze. Direct administration of 3-hydroxykynurenine, the metabolic product of KMO, caused a dose-dependent increase in depressive-like behaviors. Mice with targeted deletion of 3-hydroxyanthranilic acid dioxygenase (HAAO), the enzyme that generates quinolinic acid, were similarly challenged with LPS. Similar to KMO−/− mice, LPS failed to increase immobility during the TST. Whereas kynurenine metabolism was generally increased in behaviorally salient brain regions, a distinct shift toward KMO-dependent kynurenine metabolism occurred in the dorsal hippocampus in response to LPS. Together, these results demonstrate that KMO is a pivotal mediator of hippocampal-dependent depressive-like behaviors induced by

  15. Delayed effects of spiperone on serotonin1A receptors in the dorsal hippocampus of rats.

    PubMed Central

    Dennis, T; Blier, P; de Montigny, C

    1993-01-01

    The effects of 5-HT1A antagonists spiperone, methiothepin and BMY 7378 on [3H]-8-OH-DPAT binding were determined in vitro and ex vivo in rat hippocampus CA3 membrane preparations, and ex vivo in tissue sections of CA1 and CA3 subfields using quantitative autoradiography. In CA3 membranes from rats sacrificed 1 h or 24 h after administration of 5 mg/kg i.p. spiperone or methiothepin, no decrease in [3H]-8-OH-DPAT Bmax values approached statistical significance. Autoradiograms from identically treated rats showed significant increases in Kd values in both CA1 and CA3 hippocampal subfields 24 h but not 1 h after administration of the drugs, while no changes were observed in the dorsal raphe at either time. In vitro co-incubation of membranes with spiperone (200 or 500 nM) or methiothepin (500 nM) resulted in significant decreases in both affinity and Bmax values. In contrast, co-incubation with BMY 7378 (5 nM) increased only Kd values. GTP gamma S produced a concentration-dependent inhibition of specific [3H]8-OH-DPAT binding. At 0.1 mM of GTP gamma S, Kd values were increased three-fold and Bmax values were significantly decreased. When membranes were co-incubated with GTP gamma S and spiperone or BMY 7378, Kd values increased further. Moreover, the effects of spiperone and GTP gamma S on Bmax values were additive. It is concluded that BMY 7378 acts as a competitive antagonist at hippocampal post-synaptic 5-HT1A receptors, whereas spiperone and methiothepin exert their delayed antagonistic effects at these receptors through a non-competitive mechanism of action, possibly affecting the coupling of the receptors to their Gi/o proteins. PMID:8297925

  16. Glucose Injections into the Dorsal Hippocampus or Dorsolateral Striatum of Rats Prior to T-Maze Training: Modulation of Learning Rates and Strategy Selection

    ERIC Educational Resources Information Center

    Canal, Clinton E.; Stutz, Sonja J.; Gold, Paul E.

    2005-01-01

    The present experiments examined the effects of injecting glucose into the dorsal hippocampus or dorsolateral striatum on learning rates and on strategy selection in rats trained on a T-maze that can be solved by using either a hippocampus-sensitive place or striatum-sensitive response strategy. Percentage strategy selection on a probe trial…

  17. Glucose Injections into the Dorsal Hippocampus or Dorsolateral Striatum of Rats Prior to T-Maze Training: Modulation of Learning Rates and Strategy Selection

    ERIC Educational Resources Information Center

    Canal, Clinton E.; Stutz, Sonja J.; Gold, Paul E.

    2005-01-01

    The present experiments examined the effects of injecting glucose into the dorsal hippocampus or dorsolateral striatum on learning rates and on strategy selection in rats trained on a T-maze that can be solved by using either a hippocampus-sensitive place or striatum-sensitive response strategy. Percentage strategy selection on a probe trial…

  18. NMDA receptor-dependent synaptic plasticity in dorsal and intermediate hippocampus exhibits distinct frequency-dependent profiles.

    PubMed

    Kenney, Jana; Manahan-Vaughan, Denise

    2013-11-01

    The hippocampus may be functionally differentiated along its dorsoventral axis. In contrast to the wealth of data available on synaptic plasticity mechanisms in the dorsal hippocampus, little is known about synaptic plasticity processes in the intermediate hippocampus. Behavioral data suggest that this structure may play a distinct role in learning and memory. Here, we compared amplitudes, frequency-dependency and persistency of long-term potentiation (LTP) and long-term depression (LTD) in the dorsal (DDG) and intermediate dentate gyrus (IDG). In freely moving rats, high-frequency stimulation (HFS) at 200 Hz (10 burst of 15 stimuli) elicited LTP of similar magnitude in both structures that persisted for over 24 h. The intermediate dentate gyrus is more likely to exhibit persistent LTP than its dorsal counterpart, however: HFS at 200 Hz (3 or 1 burst(s)) or 100 Hz elicited short-term potentiation (STP) in DDG, unlike in the IDG, where LTP could be recorded for at least 4 h. Whereas low frequency stimulation (LFS) at 1 Hz elicited long-lasting LTD (>24 h) in the DDG, it had no significant effect on fEPSP profile in the IDG. LFS at 2 Hz elicited short-term depression in DDG and had no effect in IDG. LTP in both IDG and DDG required activation of N-methyl-D-aspartate receptors. Paired-pulse and input-output responses differed in IDG and DDG. Our data suggest that afferent input from the entorhinal cortex generates a different response profile in the dorsal vs. intermediate DG, which may in turn relate to their postulated distinct roles in synaptic information processing and memory formation. This article is part of the Special Issue entitled 'Glutamate Receptor-Dependent Synaptic Plasticity'. Copyright © 2013 Elsevier Ltd. All rights reserved.

  19. Acute neuroinflammation impairs context discrimination memory and disrupts pattern separation processes in hippocampus.

    PubMed

    Czerniawski, Jennifer; Guzowski, John F

    2014-09-10

    Although it is known that immune system activation can impair cognition, no study to date has linked cognitive deficits during acute neuroinflammation to dysregulation of task-relevant neuronal ensemble activity. Here, we assessed both neural circuit activity and context discrimination memory retrieval, in a within-subjects design, of male rats given systemic administration of saline or lipopolysaccharide (LPS). Rats were exposed over several days to two similar contexts: one of which was paired with weak foot shock and the other was not. After reaching criteria for discriminative freezing, rats were given systemic LPS or saline injection and tested for retrieval of context discrimination 6 h later. Importantly, LPS administration produced an acute neuroinflammatory response in dorsal hippocampus at this time (as assessed by elevation of proinflammatory cytokine mRNA levels) and abolished retrieval of the previously acquired discrimination. The impact of neuroinflammation on hippocampal CA3 and CA1 neural circuit activity was assessed using the Arc/Homer1a cellular analysis of temporal activity by fluorescence in situ hybridization imaging method. Whereas the saline-treated subjects discriminated and had low overlap of hippocampal ensembles activated in the two contexts, LPS-treated subjects did not discriminate and had greater ensemble overlap (i.e., reduced orthogonalization). Additionally, retrieval of standard contextual fear conditioning, which does not require context discrimination, was not affected by pretesting LPS administration. Together, the behavioral and circuit analyses data provide compelling evidence that LPS administration impairs context discrimination memory by disrupting cellular pattern separation processes within the hippocampus, thus linking acute neuroinflammation to disruption of specific neural circuit functions and cognitive impairment. Copyright © 2014 the authors 0270-6474/14/3412470-11$15.00/0.

  20. Acute Neuroinflammation Impairs Context Discrimination Memory and Disrupts Pattern Separation Processes in Hippocampus

    PubMed Central

    Czerniawski, Jennifer

    2014-01-01

    Although it is known that immune system activation can impair cognition, no study to date has linked cognitive deficits during acute neuroinflammation to dysregulation of task-relevant neuronal ensemble activity. Here, we assessed both neural circuit activity and context discrimination memory retrieval, in a within-subjects design, of male rats given systemic administration of saline or lipopolysaccharide (LPS). Rats were exposed over several days to two similar contexts: one of which was paired with weak foot shock and the other was not. After reaching criteria for discriminative freezing, rats were given systemic LPS or saline injection and tested for retrieval of context discrimination 6 h later. Importantly, LPS administration produced an acute neuroinflammatory response in dorsal hippocampus at this time (as assessed by elevation of proinflammatory cytokine mRNA levels) and abolished retrieval of the previously acquired discrimination. The impact of neuroinflammation on hippocampal CA3 and CA1 neural circuit activity was assessed using the Arc/Homer1a cellular analysis of temporal activity by fluorescence in situ hybridization imaging method. Whereas the saline-treated subjects discriminated and had low overlap of hippocampal ensembles activated in the two contexts, LPS-treated subjects did not discriminate and had greater ensemble overlap (i.e., reduced orthogonalization). Additionally, retrieval of standard contextual fear conditioning, which does not require context discrimination, was not affected by pretesting LPS administration. Together, the behavioral and circuit analyses data provide compelling evidence that LPS administration impairs context discrimination memory by disrupting cellular pattern separation processes within the hippocampus, thus linking acute neuroinflammation to disruption of specific neural circuit functions and cognitive impairment. PMID:25209285

  1. Temporary inactivation reveals that the CA1 region of the mouse dorsal hippocampus plays an equivalent role in the retrieval of long-term object memory and spatial memory.

    PubMed

    Stackman, Robert W; Cohen, Sarah J; Lora, Joan C; Rios, Lisa M

    2016-09-01

    Recognition of a previously experienced item or object depends upon the successful retrieval of memory for the object. The neural mechanisms that support object recognition memory in the mammalian brain are not well understood. The rodent hippocampus plays a well-established role in spatial memory, and we previously demonstrated that temporary inactivation of the mouse hippocampus impairs object memory, as assessed with a novel object preference (NOP) test. The present studies were designed to test some remaining issues regarding the contribution of the CA1 sub-region of the mouse dorsal hippocampus to long-term object memory. Specifically, we examined whether the retrieval of spatial memory (as assessed by the Morris water maze; MWM) and object recognition memory are differentially sensitive to inactivation of the CA1 region. The current study used pre-test local microinfusion of muscimol directly into the CA1 region of dorsal hippocampus to temporarily interrupt its function during the respective retrieval phases of both behavioral tasks, in order to compare the contribution of the CA1 to object memory and spatial memory. Histological analyses revealed that local intra-CA1 injection of muscimol diffused within, and not beyond, the CA1 region of dorsal hippocampus. The degree of memory retrieval impairment induced by muscimol was comparable in the two tasks, supporting the view that object memory and spatial memory depend similarly on the CA1 region of rodent hippocampus. Further, we confirmed that the muscimol-induced impairment of CA1 function is temporary. First, mice that exhibited impaired object memory retrieval immediately after intra-CA1 muscimol, subsequently exhibited unimpaired retrieval of object memory when tested 24h later. Secondly, a cohort of mice that exhibited impaired object memory retrieval after intra-CA1 muscimol later acquired spatial memory in the MWM comparable to that of control mice. Together, these results offer further support for the

  2. Reversal learning impairment and alterations in the prefrontal cortex and the hippocampus in a model of portosystemic hepatic encephalopathy.

    PubMed

    Méndez, Marta; Méndez-López, Magdalena; López, Laudino; Begega, Azucena; Aller, María Angeles; Arias, Jaime; Arias, Jorge L

    2010-09-01

    Patients with liver dysfunction often suffer from hepatic encephalopathy (HE), a neurological complication that affects attention and memory. Various experimental animal models have been used to study HE, the most frequently used being the portocaval shunt (PCS). In order to determine brain substrates of cognitive impairment in this model, we assessed reversal learning and c-Fos expression in a rat model of portosystemic derivation. PCS and sham-operated rats (SHAM) were tested for reversal learning. Brains were processed for c-Fos immunocytochemistry. The total number of c-Fos positive nuclei was quantified in the prefrontal cortex and hippocampus. The spatial reference memory task showed no differences between groups in escape latencies. The no-platform probe test showed that both the PCS and the SHAM learned the location of platform. However, the PCS group perseverated in the old target during reversal. The PCS group presented less c-Fos- positive cells in prelimbic cortex, CA1 and dentate gyrus of the dorsal hippocampus than SHAM. Overall, these results suggest that this specific model of portosystemic hepatic encephalopathy produces reversal learning impairment that could be linked to dysfunction in neuronal activity in the prefrontal cortex and hippocampus.

  3. TrkB blockade in the hippocampus after training or retrieval impairs memory: protection from consolidation impairment by histone deacetylase inhibition.

    PubMed

    Blank, Martina; Petry, Fernanda S; Lichtenfels, Martina; Valiati, Fernanda E; Dornelles, Arethuza S; Roesler, Rafael

    2016-03-01

    Relatively little is known about the requirement of signaling initiated by brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrkB), in the early phases of memory consolidation, as well as about its possible functional interactions with epigenetic mechanisms. Here we show that blocking TrkB in the dorsal hippocampus after learning or retrieval impairs retention of memory for inhibitory avoidance (IA). More importantly, the impairing effect of TrkB antagonism on consolidation was completely prevented by the histone deacetylase (HDAC) inhibitor sodium butyrate (NaB). Male Wistar rats were given an intrahippocampal infusion of saline (SAL) or NaB before training, followed by an infusion of either vehicle (VEH) or the selective TrkB antagonist ANA-12 immediately after training. In a second experiment, the infusions were administered before and after retrieval. ANA-12 after either training or retrieval produced a significant impairment in a subsequent memory retention test. Pretraining administration of NaB prevented the effect of ANA-12, although NaB given before retrieval did not alter the impairment resulting from TrkB blockade. The results indicate that inhibition of BDNF/TrkB in the hippocampus can hinder consolidation and reconsolidation of IA memory. However, TrkB activity is not required for consolidation in the presence of NaB, suggesting that a dysfunction in BDNF/TrkB signaling can be fully compensated by HDAC inhibition to allow hippocampal memory formation.

  4. Uremia-caused changes of ghrelin system in hippocampus may be associated with impaired cognitive function of hippocampus.

    PubMed

    Lv, Zhian; Gao, Jie; Wang, Li; Chen, Zhao; Yuan, Haozheng; Ma, Xiaoqin; Lu, Jiamei; Lv, Jianrui; Wu, Xili; Zhang, Lei; Wei, Linting; Xue, Rongliang; Fu, Rongguo; Ma, Liqun

    2016-05-01

    Hippocampus plays an important role in spatial learning and memory. Ghrelin, a brain-gut peptide, participates in the mnestic functions of hippocampus through its receptor growth hormone secretagogue receptor (GHS-R) distributed in hippocampus. This study was to investigate whether there was a correlation between the changes of ghrelin system in hippocampus and the spatial cognitive impairment caused by chronic renal failure (CRF). Sprague-Dawley rats (male, 180 ± 10 g, 7-8 weeks old) were randomly classified into CRF group and control group (n = 18 per group). The CRF model was constructed by 5/6 nephrectomy and the controls treated with sham operation. By the 8th week after the surgery, the spatial cognitive function of rats was assessed by Morris water-maze test (MWM), the protein expression of ghrelin and GHS-R in the hippocampus by immunohistochemistry, and the mRNA expression by real-time PCR. Statistical analysis was performed using ANOVA, Student-Newman-Keuls-q test and Pearson correlation analysis, and P < 0.05 was considered significant. Compared with the controls, the time spent in "platform" quadrant (TSPQ) of rats with CRF was decreased, but the escape latency (EL) was increased significantly in MWM, and meanwhile the protein and mRNA expression of ghrelin and GHS-R in hippocampus was also increased significantly (P < 0.05 or P < 0.01). Correlation analysis suggested that the TSPQ was negatively but the EL was positively correlated with the mRNA expression of ghrelin and GHS-R (P < 0.01). The CRF-caused changes of ghrelin system in hippocampus might be correlated with the CRF-caused cognitive function impairment.

  5. Delayed wave of c-Fos expression in the dorsal hippocampus involved specifically in persistence of long-term memory storage

    PubMed Central

    Katche, Cynthia; Bekinschtein, Pedro; Slipczuk, Leandro; Goldin, Andrea; Izquierdo, Ivan A.; Cammarota, Martin; Medina, Jorge H.

    2009-01-01

    Memory formation is a temporally graded process during which transcription and translation steps are required in the first hours after acquisition. Although persistence is a key characteristic of memory storage, its mechanisms are scarcely characterized. Here, we show that long-lasting but not short-lived inhibitory avoidance long-term memory is associated with a delayed expression of c-Fos in the hippocampus. Importantly, this late wave of c-Fos is necessary for maintenance of inhibitory avoidance long-term storage. Moreover, inhibition of transcription in the dorsal hippocampus 24 h after training hinders persistence but not formation of long-term storage. These findings indicate that a delayed phase of transcription is essential for maintenance of a hippocampus-dependent memory trace. Our results support the hypothesis that recurrent rounds of consolidation-like events take place late after learning in the dorsal hippocampus to maintain memories. PMID:20018662

  6. Temporary inhibition of dorsal or ventral hippocampus by muscimol: distinct effects on measures of innate anxiety on the elevated plus maze, but similar disruption of contextual fear conditioning.

    PubMed

    Zhang, Wei-Ning; Bast, Tobias; Xu, Yan; Feldon, Joram

    2014-04-01

    Studies in rats, involving hippocampal lesions and hippocampal drug infusions, have implicated the hippocampus in the modulation of anxiety-related behaviors and conditioned fear. The ventral hippocampus is considered to be more important for anxiety- and fear-related behaviors than the dorsal hippocampus. In the present study, we compared the role of dorsal and ventral hippocampus in innate anxiety and classical fear conditioning in Wistar rats, examining the effects of temporary pharmacological inhibition by the GABA-A agonist muscimol (0.5 ug/0.5 ul/side) in the elevated plus maze and on fear conditioning to a tone and the conditioning context. In the elevated plus maze, dorsal and ventral hippocampal muscimol caused distinct behavioral changes. The effects of ventral hippocampal muscimol were consistent with suppression of locomotion, possibly accompanied by anxiolytic effects, whereas the pattern of changes caused by dorsal hippocampal muscimol was consistent with anxiogenic effects. In contrast, dorsal and ventral hippocampal muscimol caused similar effects in the fear conditioning experiments, disrupting contextual, but not tone, fear conditioning.

  7. Encoding and retrieval along the long axis of the hippocampus and their relationships with dorsal attention and default mode networks: The HERNET model.

    PubMed

    Kim, Hongkeun

    2015-04-01

    The encoding of sensory input is intertwined with external attention, whereas retrieval is intrinsically related to internal attention. This study proposes a model in which the encoding of sensory input involves mainly the anterior hippocampus and the external attention network, whereas retrieval, the posterior hippocampus and the internal attention network. This model is referred to as the HERNET (hippocampal encoding/retrieval and network) model. Functional neuroimaging studies have identified two intrinsic large-scale networks closely associated with external and internal attention, respectively. The dorsal attention network activates during any externally oriented mental activity, whereas the default mode network shows increased activity during internally oriented mental activity. Therefore, the HERNET model may predict the activation of the anterior hippocampus and the dorsal attention network during the encoding and activation of the posterior hippocampus and the default mode network during retrieval. To test this prediction, this study provides a meta-analysis of three memory-imaging paradigms: subsequent memory, laboratory-based recollection, and autobiographical memory retrieval. The meta-analysis included 167 individual studies and 2,856 participants. The results provide support for the HERNET model and suggest that the anterior-posterior gradient of encoding and retrieval includes amygdala regions. More broadly, humans continuously oscillate between external and internal attention and thus between encoding and retrieval processes. These oscillations may involve repetitive and spontaneous activity switching between the anterior hippocampus/dorsal attention network and the posterior hippocampus/default mode network.

  8. Cannabinoid CB1 receptors of the dorsal hippocampus are important for induction of conditioned place preference (CPP) but do not change morphine CPP.

    PubMed

    Zarrindast, Mohammad-Reza; Nouri, Maryam; Ahmadi, Shamseddin

    2007-08-13

    Interactions between cannabinoid and opioid systems have been reported in many studies. In the present study, we have investigated influence of cannabinoid CB1 receptor mechanism on the acquisition of conditioned place preference (CPP) induced by morphine in male Wistar rats. The cannabinoid CB1 receptor agonist (WIN55,212-2) and antagonist (AM251) were injected bilaterally into the dorsal hippocampus. Morphine and naloxone were injected subcutaneously (s.c.). The conditioning treatments with injections of morphine (6 and 9 mg/kg) induced a CPP for the drug-associated place. When administered into the dorsal hippocampus, WIN55,212-2 (1 microg/rat) induced CPP, but significantly did not alter CPP induced by a sub-effective dose of morphine (3 mg/kg). Moreover, administration of different doses of AM251 (50 and 100 ng/rat) into the dorsal hippocampus induced CPP, while did not change CPP by the sub-effective dose of morphine. Naloxone alone (1 mg/kg) induced conditioned place aversion (CPA). The drug (0.5 and 1 mg/kg) also caused CPA when co-administered with WIN55,212-2 (1 microg/rat). These results suggest that endocannabinoid system in the dorsal hippocampus is important for the CPP paradigm. However, agents did not alter morphine-induced CPP.

  9. Interaction between the Basolateral Amygdala and Dorsal Hippocampus Is Critical for Cocaine Memory Reconsolidation and Subsequent Drug Context-Induced Cocaine-Seeking Behaviorin Rats

    ERIC Educational Resources Information Center

    Wells, Audrey M.; Lasseter, Heather C.; Xie, Xiaohu; Cowhey, Kate E.; Reittinger, Andrew M.; Fuchs, Rita A.

    2011-01-01

    Contextual stimulus control over instrumental drug-seeking behavior relies on the reconsolidation of context-response-drug associative memories into long-term memory storage following retrieval-induced destabilization. According to previous studies, the basolateral amygdala (BLA) and dorsal hippocampus (DH) regulate cocaine-related memory…

  10. Interaction between the Basolateral Amygdala and Dorsal Hippocampus Is Critical for Cocaine Memory Reconsolidation and Subsequent Drug Context-Induced Cocaine-Seeking Behaviorin Rats

    ERIC Educational Resources Information Center

    Wells, Audrey M.; Lasseter, Heather C.; Xie, Xiaohu; Cowhey, Kate E.; Reittinger, Andrew M.; Fuchs, Rita A.

    2011-01-01

    Contextual stimulus control over instrumental drug-seeking behavior relies on the reconsolidation of context-response-drug associative memories into long-term memory storage following retrieval-induced destabilization. According to previous studies, the basolateral amygdala (BLA) and dorsal hippocampus (DH) regulate cocaine-related memory…

  11. Anxiogenic effects in the rat elevated plus-maze of 5-HT(2C) agonists into ventral but not dorsal hippocampus.

    PubMed

    Alves, S H; Pinheiro, G; Motta, V; Landeira-Fernandez, J; Cruz, A P M

    2004-02-01

    The effect of the non-selective 5-HT2C receptor agonist trifluoromethyl-phenylpiperazine (TFMPP, 0.75, 1.5 and 3.0 microg) and the preferential 5-HT2C agonist 6-chloro-2(1-piperazinyl)pyrazine (MK-212, 0.1, 0.3 and 1.0 microg) microinjected into the ventral or dorsal hippocampus was investigated in anxiety measures of rats exposed to the elevated plus-maze test. Ventral hippocampal (VH) microinjections of the 0.75 or 1.5 microg doses of TFMPP reduced open-arm exploration without affecting the number of closed-arm entries, indicating a selective anxiogenic profile. The highest dose (3.0 microg) reduced open- and closed-arm entries, suggesting interference in locomotor activity. The 0.1 microg dose of MK-212 also caused a selective anxiogenic effect when microinjected into the ventral hippocampus, without disturbing locomotor activity. Microinjections of the two higher doses of MK-212 (0.3 or 1.0 microg) into the ventral hippocampus led to a decrease of exploration in both arms of the maze. In contrast to the anxiogenic effect observed in the VH, neither TFMPP nor MK-212 significantly changed anxiety measures when microinjected into the dorsal hippocampus. These results suggest that activation of 5-HT2C postsynaptic receptors located in the ventral, but not in the dorsal, hippocampus play an important role in anxiety triggered by the elevated plus-maze test.

  12. The hippocampus and dorsal raphe nucleus are key brain areas associated with the antidepressant effects of lithium augmentation of desipramine.

    PubMed

    Cussotto, Sofia; Cryan, John F; O'Leary, Olivia F

    2017-03-27

    Approximately 50% of depressed individuals fail to achieve remission with first-line antidepressant drugs and a third remain treatment-resistant. When first-line antidepressant treatment is unsuccessful, second-line strategies include dose optimisation, switching to another antidepressant, combination with another antidepressant, or augmentation with a non-antidepressant medication. Much of the evidence for the efficacy of augmentation strategies comes from studies using lithium to augment the effects of tricyclic antidepressants. The neural circuitry underlying the therapeutic effects of lithium augmentation is not yet fully understood. Recently, we reported that chronic treatment with a combination of lithium and the antidepressant desipramine, exerted antidepressant-like behavioural effects in a mouse strain (BALB/cOLaHsd) that did not exhibit an antidepressant-like behavioural response to either drug alone. In the present study, we used this model in combination with ΔFosB/FosB immunohistochemistry to identify brain regions chronically affected by lithium augmentation of desipramine when compared to either treatment alone. The data suggest that the dorsal raphe nucleus and the CA3 regions of the dorsal hippocampus are key nodes in the neural circuitry underlying antidepressant action of lithium augmentation of desipramine. These data give new insight into the neurobiology underlying the mechanism of lithium augmentation in the context of treatment-resistant depression.

  13. Analysis of activity and motor coordination in rats undergoing stereotactic surgery and implantation of a cannula into the dorsal hippocampus.

    PubMed

    Hernández-López, F; Rodríguez-Landa, J F; Puga-Olguín, A; Germán-Ponciano, L J; Rivadeneyra-Domínguez, E; Bernal-Morales, B

    2016-05-05

    Stereotactic surgery is used to place electrodes or cannulas in the brain in order to study the function of several brain structures in preclinical research. The hippocampus has been extensively studied with this methodology due to its involvement in a wide range of neurological, cognitive, emotional, and affective disorders. However, the effects of stereotactic surgery on coordination and motor activity should be evaluated in order to determine whether this surgical procedure causes any neurological alterations that may bias the results of studies incorporating this technique. We evaluated the effects of stereotactic surgery and implantation of a cannula into the hippocampus of female Wistar rats on the motor activity, forced swim, and rotarod tests. The stage of the oestrous cycle was included in the statistical analysis. Stereotactic surgery had no impact on any of the motor activity variables assessed in the open field (squares crossed, time spent in grooming, and rearing), forced swim (turning behaviour, lateral swimming, latency to first immobility, and time spent immobile), and rotarod (latency to fall) tests, compared with intact rats. Regardless of surgical manipulation, rats in the metestrus and diestrus stages crossed a greater number of squares and displayed longer immobility times than those in the proestrus and estrus stages. Stereotactic surgery for cannula placement in the dorsal hippocampus does not affect coordination and motor activity in rats. We can therefore conclude that this procedure has no neurological complications that may interfere in the interpretation of results of studies applying this technique. Copyright © 2016 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.

  14. STRESS-INDUCED CHANGES IN EXTRACELLULAR DOPAMINE AND SEROTONIN IN THE MEDIAL PREFRONTAL CORTEX AND DORSAL HIPPOCAMPUS OF PRENATALLY MALNOURISHED RATS

    PubMed Central

    Mokler, David J.; Torres, Olga I.; Galler, Janina R.; Morgane, Peter J.

    2009-01-01

    Prenatal protein malnutrition continues to be a significant problem in the world today. Exposure to prenatal protein malnutrition increases the risk of a number of neuropsychiatric disorders in adulthood including depression, schizophrenia and attentional deficit disorder. In the present experiment we have examined the effects of stress on extracellular serotonin (5-HT) and dopamine in the medial prefrontal cortex and dorsal hippocampus of rats exposed in utero to protein malnutrition. The medial prefrontal cortex and dorsal hippocampus were chosen as two limbic forebrain regions involved in learning and memory, attention and the stress response. Extracellular 5-HT and dopamine were determined in the medial prefrontal cortex and dorsal hippocampus of adult male Sprague-Dawley rats using dual probe in vivo microdialysis. Basal extracellular 5-HT did not differ between malnourished and well-nourished controls in either the medial prefrontal cortex or the dorsal hippocampus. Basal extracellular dopamine was significantly decreased in the medial prefrontal cortex of malnourished animals. Restraint stress (20 m) produced a significant rise in extracellular dopamine in the medial prefrontal cortex of well-nourished rats but did not alter release in malnourished rats. In malnourished rats, stress produced an increase in 5-HT in the hippocampus, whereas stress produced a decrease in 5-HT in the hippocampus of well-nourished rats. These data demonstrate that prenatal protein malnutrition alters dopaminergic neurotransmission in the medial prefrontal cortex as well as altering the dopaminergic and serotonergic response to stress. These changes may provide part of the bases for alterations in malnourished animals’ response to stress. PMID:17368432

  15. Stress-induced changes in extracellular dopamine and serotonin in the medial prefrontal cortex and dorsal hippocampus of prenatally malnourished rats.

    PubMed

    Mokler, David J; Torres, Olga I; Galler, Janina R; Morgane, Peter J

    2007-05-07

    Prenatal protein malnutrition continues to be a significant problem in the world today. Exposure to prenatal protein malnutrition increases the risk of a number of neuropsychiatric disorders in adulthood including depression, schizophrenia and attentional deficit disorder. In the present experiment, we have examined the effects of stress on extracellular serotonin (5-HT) and dopamine in the medial prefrontal cortex and dorsal hippocampus of rats exposed in utero to protein malnutrition. The medial prefrontal cortex and dorsal hippocampus were chosen as two limbic forebrain regions involved in learning and memory, attention and the stress response. Extracellular 5-HT and dopamine were determined in the medial prefrontal cortex and dorsal hippocampus of adult male Sprague-Dawley rats using dual probe in vivo microdialysis. Basal extracellular 5-HT did not differ between malnourished and well-nourished controls in either the medial prefrontal cortex or the dorsal hippocampus. Basal extracellular dopamine was significantly decreased in the medial prefrontal cortex of malnourished animals. Restraint stress (20 m) produced a significant rise in extracellular dopamine in the medial prefrontal cortex of well-nourished rats but did not alter release in malnourished rats. In malnourished rats, stress produced an increase in 5-HT in the hippocampus, whereas stress produced a decrease in 5-HT in the hippocampus of well-nourished rats. These data demonstrate that prenatal protein malnutrition alters dopaminergic neurotransmission in the medial prefrontal cortex as well as alters the dopaminergic and serotonergic response to stress. These changes may provide part of the bases for alterations in malnourished animals' response to stress.

  16. Inhibition of Rac1 Activity in the Hippocampus Impairs the Forgetting of Contextual Fear Memory.

    PubMed

    Jiang, Lizhu; Mao, Rongrong; Zhou, Qixin; Yang, Yuexiong; Cao, Jun; Ding, Yuqiang; Yang, Yuan; Zhang, Xia; Li, Lingjiang; Xu, Lin

    2016-03-01

    Fear is crucial for survival, whereas hypermnesia of fear can be detrimental. Inhibition of the Rac GTPase is recently reported to impair the forgetting of initially acquired memory in Drosophila. Here, we investigated whether inhibition of Rac1 activity in rat hippocampus could contribute to the hypermnesia of contextual fear. We found that spaced but not massed training of contextual fear conditioning caused inhibition of Rac1 activity in the hippocampus and heightened contextual fear. Furthermore, intrahippocampal injection of the Rac1 inhibitor NSC23766 heightened contextual fear in massed training, while Rac1 activator CN04-A weakened contextual fear in spaced training rats. Our study firstly demonstrates that contextual fear memory in rats is actively regulated by Rac1 activity in the hippocampus, which suggests that the forgetting impairment of traumatic events in posttraumatic stress disorder may be contributed to the pathological inhibition of Rac1 activity in the hippocampus.

  17. Dorsal hippocampal contributions to unimodal contextual conditioning.

    PubMed

    Otto, Tim; Poon, Patrick

    2006-06-14

    Although there is general consensus that the hippocampus is not critically involved in the acquisition of fear conditioned to an explicit conditioned stimulus (CS), the extent to which the hippocampus participates in contextual fear conditioning remains unclear. To further characterize the potential role of the hippocampus in contextual fear conditioning, the present experiments examined the effect of excitotoxic lesions of dorsal hippocampus on the acquisition of a novel contextual fear conditioning paradigm in which a unimodal (olfactory) cue served to disambiguate discrete "contexts" within a single behavioral training chamber. Selective lesions of dorsal hippocampus severely attenuated olfactory contextual conditioning without affecting conditioning to an explicit auditory or olfactory CS. Additional experiments indicate that these contextual conditioning deficits cannot be attributed to a lesion-induced decrement in olfactory perception, a preferential impairment of "weak" forms of conditioning, or hyperactivity. Thus, the hippocampus appears to contribute importantly to the acquisition of fear conditioned to explicitly nonspatial, unimodal, temporally, and spatially diffuse contextual stimuli.

  18. Improvement of two-way active avoidance memory requires protein kinase a activation and brain-derived neurotrophic factor expression in the dorsal hippocampus.

    PubMed

    Datta, Subimal; Siwek, Donald F; Huang, Max P

    2009-07-01

    Previous studies have shown that two-way active avoidance (TWAA) memory processing involves a functional interaction between the pontine wave (P wave) generator and the CA3 region of the dorsal hippocampus (DH-CA3). The present experiments examined whether the interaction between P wave generator activity and the DH-CA3 involves the intracellular protein kinase A (PKA) signaling system. In the first series of experiments, rats were subjected to a session of TWAA training followed immediately by bilateral microinjection of either the PKA activation inhibitor (KT-5720) or vehicle control into the DH-CA3 and tested for TWAA memory 24 h later. The results indicated that immediate KT-5720 infusion impaired improvement of TWAA performance. Additional experiments showed that KT-5720 infusion also blocked TWAA training-induced BDNF expression in the DH-CA3. Together, these findings suggest that the PKA activation and BDNF expression in the DH-CA3 is essential for the improvement of TWAA memory.

  19. The mTOR and canonical Wnt signaling pathways mediate the mnemonic effects of progesterone in the dorsal hippocampus.

    PubMed

    Fortress, Ashley M; Heisler, John D; Frick, Karyn M

    2015-05-01

    Although much is known about the neural mechanisms responsible for the mnemonic effects of 17β-estradiol (E2 ), very little is understood about the mechanisms through which progesterone (P4 ) regulates memory. We previously showed that intrahippocampal infusion of P4 in ovariectomized female mice enhances object recognition (OR) memory consolidation in a manner dependent on activation of dorsal hippocampal ERK and mTOR signaling. However, the role of specific progesterone receptors (PRs) in mediating the effects of progesterone on memory consolidation and hippocampal cell signaling are unknown. Therefore, the goals of this study were to investigate the roles of membrane-associated and intracellular PRs in mediating hippocampal memory consolidation, and identify downstream cell signaling pathways activated by PRs. Membrane-associated PRs were targeted using bovine serum albumin-conjugated progesterone (BSA-P), and intracellular PRs (PR-A, PR-B) were targeted using the intracellular PR agonist R5020. Immediately after OR training, ovariectomized mice received bilateral dorsal hippocampal infusion of vehicle, P4 , BSA-P, or R5020. OR memory consolidation was enhanced by P4 , BSA-P, and R5020. However, only P4 and BSA-P activated ERK and mTOR signaling. Furthermore, dorsal hippocampal infusion of the ERK inhibitor U0126 blocked the memory-enhancing effects of BSA-P, but not R5020. The intracellular PR antagonist RU486 blocked the memory-enhancing effects of R5020, but not BSA-P. Interestingly, P4 robustly activated canonical Wnt signaling in the dorsal hippocampus, which is consistent with our recent findings that canonical Wnt signaling is necessary for OR memory consolidation. R5020, but not BSA-P, also elicited a modest increase in canonical Wnt signaling. Collectively, these data suggest that activation of ERK signaling is necessary for membrane-associated PRs to enhance OR, and indicate a role for canonical Wnt signaling in the memory-enhancing effects of

  20. Influence of N-methyl D-aspartate receptor mechanism on WIN55,212-2-induced amnesia in rat dorsal hippocampus.

    PubMed

    Jamali-Raeufy, Nida; Nasehi, Mohammad; Zarrindast, Mohammad Reza

    2011-10-01

    In this study, we investigated the effects of both N-methyl D-aspartate (NMDA) and MK-801 on WIN55,212-2(WIN)-induced amnesia in rats. Step-through inhibitory avoidance of memory was used to examine the retrieval of memory, 24 h after training. All drugs were injected bilaterally into the dorsal hippocampus (intra-CA1) of rats. Pretraining and posttraining or pretesting administration of the nonselective CB1/CB2 receptor agonist, WIN (0.5 µg/rat), decreased the step-through latency. However, amnesia induced by pretraining or posttraining injections of WIN was reversed by a pretest administration of WIN (0.25 and 0.5 µg/rat). Pretest microinjections of different doses of NMDA (0.1, 0.5, and 1 µg/rat) elicited no response, but NMDA (0.5 and 1 µg/rat) did induce full recovery from amnesia induced by WIN (0.5 µg/rat). The posttraining and pretest injection of a higher dose of the NMDA receptor antagonist, MK801 (MK; 4 µg/rat), caused an impairment in the memory retrieval. However, amnesia induced by posttraining injections of MK (4 µg/rat) was reversed by a pretest administration of MK (4 µg/rat). In addition, pretest administration of different doses of the antagonist (2 and 4 µg/rat) induced full recovery of WIN-induced amnesia, but did not influence memory recovery in the subjects, which had received posttraining (0.5 µg/rat) and pretest WIN (0.25 and 0.5 µg/rat). Pretesting coadministration of ineffective doses of WIN (0.1 µg/rat) with NMDA (0.1 µg/rat), but not with MK (1 µg/rat), restored WIN-induced (0.5 µg/rat) amnesia. It can be concluded that the NMDA receptor mechanism located in the dorsal hippocampus may be involved in WIN-induced amnesia.

  1. A map of LTP-related synaptic changes in dorsal hippocampus following unsupervised learning.

    PubMed

    Cox, Conor D; Rex, Christopher S; Palmer, Linda C; Babayan, Alex H; Pham, Danielle T; Corwin, Samantha D; Trieu, Brian H; Gall, Christine M; Lynch, Gary

    2014-02-19

    Recent work showed that unsupervised learning of a complex environment activates synaptic proteins essential for the stabilization of long-term potentiation (LTP). The present study used automated methods to construct maps of excitatory synapses associated with high concentrations of one of these LTP-related proteins [CaMKII phosphorylated at T286/287, (pCaMKII)]. Labeling patterns across 42 sampling zones covering entire cross sections through rostral hippocampus were assessed for two groups of rats that explored a novel two-room arena for 30 min, with or without a response contingency involving mildly aversive cues. The number of pCaMKII-immunopositive (+) synapses was highly correlated between the two groups for the 21 sampling zones covering the dentate gyrus, CA3c/hilus, and apical dendrites of field CA1, but not for the remainder of the cross section. The distribution of pCaMKII+ synapses in the large uncorrelated segment differed markedly between the groups. Subtracting home-cage values removed high scores (i.e., sampling zones with a high percentage of pCaMKII+ contacts) in the negative contingency group, but not in the free-exploration animals. Three sites in the latter had values that were markedly elevated above other fields. These mapping results suggest that encoding of a form of memory that is dependent upon rostral hippocampus reliably occurs at high levels in discrete anatomical zones, and that this regionally differentiated response is blocked when animals are inhibited from freely exploring the environment by the introduction of a mildly aversive stimulus.

  2. Dorsal sensory impairment in hands and feet of people affected by Hansen's disease in Israel.

    PubMed

    Wexler, Ruth; Melchior, Hanna

    2007-12-01

    Sensory testing in people affected by Hansen's disease is usually performed on palms and soles only. In Israel, both palmar/plantar and dorsal aspects of limbs are routinely tested. The aim of this study was to describe the magnitude of dorsal sensory impairment (SI) in limbs and compare the frequency of SI on palms and soles with that on the dorsum of hands and feet. In a cross-sectional study, limbs of 140 patients registered at The Israel Hansen's Disease Centre during the years 1999-2003 were tested for their sensory status. Both palmar/plantar and dorsal aspects were tested using Semmes-Weinstein monofilaments. SI was defined as not feeling stimuli applied with the 2 g monofilament. SI was detected on the dorsum in 43% of sites on hands and only in 27% on palms. 64% of sites on dorsum of feet had SI compared to 53% on the soles. SI was detected in up to 18% in hands with no palmar SI, and in 6% of feet with no plantar SI. Furthermore, SI on palms and soles was found to be accompanied by dorsal SI in all hands and in 97% of feet. SI on dorsum of limbs occurs more frequently than SI on palms and soles. Therefore sensory testing should also consider inclusion of the dorsal aspect of hands and feet.

  3. Involvement of dopamine receptors within the dorsal hippocampus in suppression of the formalin-induced orofacial pain.

    PubMed

    Shamsizadeh, Ali; Pahlevani, Pouyan; Haghparast, Amir; Moslehi, Maryam; Zarepour, Leila; Haghparast, Abbas

    2013-12-01

    It is widely established that the dopaminergic system has profound effects on pain modulation in different regions of the brain including the hippocampus, the salient area for brain functions. The orofacial region is one of the most densely innervated (by the trigeminal nerves) areas of the body susceptible to acute and chronic pains. In this study, we tried to examine the effects of dopamine receptors located in the dorsal hippocampus (CA1) region upon the modulation of orofacial pain induced by the formalin test. To induce orofacial pain in male Wistar rats, 50μl of 1% formalin was subcutaneously injected into the upper lip. In control and experimental groups, two guide cannulae were stereotaxically implanted in the CA1, and SKF-38393 (0.25, 0.5, 1 and 2μg/0.5μl saline) as a D1-like receptor agonist, SCH-23390 (1μg/0.5μl saline) as a D1-like receptor antagonist, Quinpirole (0.5, 1, 2 and 4μg/0.5μl saline) as a D2-like receptor agonist and Sulpiride(3μg/0.5μl DMSO) as a D2-like receptor antagonist or vehicles were microinjected. For induction of orofacial pain, 50μl of 1% formalin was subcutaneously injected into the left side of the upper lip. Results indicated that SKF-38393 at the dose of 1 and 2μg significantly reduced pain during the first and second phases of observed pain while SCH-23390 reversed such analgesic effect. Moreover, there is a significant difference between groups in which animals received 2 and 4μg quinpirole or vehicle in the first phase (early phase) of pain. The three high doses of this compound (1, 2 and 4μg) appeared to have an analgesic effect during the second (late) phase. Furthermore, Sulpiride could potentially reverse the observed analgesic effects already induced by an agonist. Current findings suggest that the dorsal hippocampal dopamine receptors exert an analgesic effect during the orofacial pain test.

  4. [Posttrial injections of corticosterone in dorsal hippocampus of the BALB/c mouse facilitate extinction of appetitive operant conditioning in the Skinner box].

    PubMed

    Micheau, J; Destrade, C; Soumireu-Mourat, B

    1982-06-28

    Corticosterone was injected bilaterally into the dorsal hippocampus of BALB/c Mice immediately after the first extinction session of an operant conditioning in a Skinner box. Compared with the control animals the Mice that received 1 or 0.1 microgram corticosterone exhibited 24 hrs. later, faster extinction of this conditioning. With a 0.01 microgram dose of corticosterone in each hippocampus we obtained an accelerated extinction during the session. These data suggest that corticosterone modulates hippocampal mechanisms involved in memory processes.

  5. Overexpression of EphB2 in hippocampus rescues impaired NMDA receptors trafficking and cognitive dysfunction in Alzheimer model.

    PubMed

    Hu, Rui; Wei, Pan; Jin, Lu; Zheng, Teng; Chen, Wen-Yu; Liu, Xiao-Ya; Shi, Xiao-Dong; Hao, Jing-Ru; Sun, Nan; Gao, Can

    2017-03-30

    Alzheimer's disease (AD) is a progressive neurodegenerative disease, which affects more and more people. But there is still no effective treatment for preventing or reversing the progression of the disease. Soluble amyloid-beta (Aβ) oligomers, also known as Aβ-derived diffusible ligands (ADDLs) play an important role in AD. Synaptic activity and cognition critically depend on the function of glutamate receptors. Targeting N-methyl-D-aspartic acid (NMDA) receptors trafficking and its regulation is a new strategy for AD early treatment. EphB2 is a key regulator of synaptic localization of NMDA receptors. Aβ oligomers could bind to the fibronectin repeats domain of EphB2 and trigger EphB2 degradation in the proteasome. Here we identified that overexpression of EphB2 with lentiviral vectors in dorsal hippocampus improved impaired memory deficits and anxiety or depression-like behaviors in APPswe/PS1-dE9 (APP/PS1) transgenic mice. Phosphorylation and surface expression of GluN2B-containing NMDA receptors were also improved. Overexpression of EphB2 also rescued the ADDLs-induced depletion of the expression of EphB2 and GluN2B-containing NMDA receptors trafficking in cultured hippocampal neurons. These results suggest that improving the decreased expression of EphB2 and subsequent GluN2B-containing NMDA receptors trafficking in hippocampus may be a promising strategy for AD treatment.

  6. [Statistical analysis of the activity of pyramidal cells in the dorsal hippocampus of the rabbit].

    PubMed

    Bassant, M H

    1976-06-01

    The spontaneous activity of CA1 pyramidal cells was reduced with microelectrodes from the hippocampus of curarized adult rabbits under painless fixation. A statistical analysis of the data was made by a computer, using a program developed to process time interval series. 1. Various temporal patterns of discharge were observed. A classification into 5 distinct patterns could be disclosed, based on statistical parameters, particularly expectation density, joint interval histogram and interspike interval histogram. 2. The recorded neurones were distributed unequally in these groups, the distribution varying with sleep and wakefulness. 3. Some firing patterns prevailed during wakefulness and some during sleep, but all of them were observed in both states and no one was considered specific to one state. 4. The variability in neuronal discharge was estimated. "Stable" cells (60%) exhibited only one firing pattern. "Unstable" cells (40%) exhibited either two (82%) or three (18%) types of firing. 5. 65% of the cells recorded during waking and then during sleep shifted their firing pattern. The majority of the other units (35%), which kept the same pattern of discharge, were already stable during waking. Hence, they exhibited only one firing pattern and did not appear to be affected by sleep or waking.

  7. Apoptotic Process Induced by Oxaliplatin in Rat Hippocampus Causes Memory Impairment.

    PubMed

    Bianchi, Enrica; Di Cesare Mannelli, Lorenzo; Micheli, Laura; Farzad, Mersedez; Aglianò, Margherita; Ghelardini, Carla

    2017-01-01

    Aspects of memory involved in cognitive mechanisms were investigated in rat after oxaliplatin (OX) chemotherapy using animal behavioural assessment of passive avoidance and social learning paradigms, which are both hippocampus-sensitive. Rodents, previously subjected to 2-week OX treatment, showed passive avoidance and social learning impairment and apoptotic processes in the hippocampus. Apoptosis rate significantly increased in cultured hippocampal cells exposed to OX at increasing doses, and this effect was dose-dependent. Ex vivo experiments showed that cell damage and apoptosis were blocked in the hippocampus from OX rats cotreated with copper sulphate (CS) which precludes OX transport inside the cell. In vivo, passive avoidance and social learning impairment could not be observed in OX rats co-administered with CS. Thus, a site of action of OX treatment on memory impairment appears to be located at the hippocampus. These findings strongly support that cellular damage induced by OX in rodent hippocampus underlies the weakening of some memory functions. © 2016 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

  8. Brain tissue oxygen amperometry in behaving rats demonstrates functional dissociation of dorsal and ventral hippocampus during spatial processing and anxiety

    PubMed Central

    McHugh, Stephen B; Fillenz, Marianne; Lowry, John P; Rawlins, J Nicolas P; Bannerman, David M

    2011-01-01

    Traditionally, the function of the hippocampus (HPC) has been viewed in unitary terms, but there is growing evidence that the HPC is functionally differentiated along its septotemporal axis. Lesion studies in rodents and functional brain imaging in humans suggest a preferential role for the septal HPC in spatial learning and a preferential role for the temporal HPC in anxiety. To better enable cross-species comparison, we present an in vivo amperometric technique that measures changes in brain tissue oxygen at high temporal resolution in freely-moving rats. We recorded simultaneously from the dorsal (septal; dHPC) and ventral (temporal; vHPC) HPC during two anxiety tasks and two spatial tasks on the radial maze. We found a double-dissociation of function in the HPC, with increased vHPC signals during anxiety and increased dHPC signals during spatial processing. In addition, dHPC signals were modulated by spatial memory demands. These results add a new dimension to the growing consensus for a differentiation of HPC function, and highlight tissue oxygen amperometry as a valuable tool to aid translation between animal and human research. PMID:21105915

  9. Prominent differences in sharp wave-Ripples and complex spike bursts between the dorsal and the ventral rat hippocampus.

    PubMed

    Kouvaros, Stylianos; Papatheodoropoulos, Costas

    2017-04-05

    Functions of the hippocampus are segregated along its long axis and emerging evidence shows that the local circuitry is specialized accordingly. Sharp waves (SPWs) and ripples are a basic hippocampal network activity implicated in memory processing. Using recordings from the CA1 field of both dorsal (DH) and ventral (VH) rat hippocampal slices we found that SPWs are larger, shorter and occur much more frequently in the VH than in the DH. Clusters of SPWs (i.e. multiple consecutive events grouped in sequences that depend on NMDA receptors) occur with higher probability in the VH and the frequency of occurrence of consecutive intra-cluster events is higher in the VH (∼10Hz) than in the DH (∼5Hz). The ripple oscillation displays higher amplitude and frequency in the VH than in DH and the associated multiunit firing peaks at a later phase of the ripple waves in the VH than in the DH. Isolated unit complex spike bursts display a significantly lower number of spikes and longer inter-spike intervals in the VH than in the DH suggesting that the synaptically driven neuronal excitability is lower in the VH. We propose that to some extent these differences result from the relatively higher network excitability of the VH compared with DH. Furthermore, they might reflect specializations that provide the local circuitries of the DH and VH with the required optimal ability for synaptic plasticity and might also suggest that the VH could be a favored site of SPW-Rs initiation.

  10. Parallel memory processing by the CA1 region of the dorsal hippocampus and the basolateral amygdala.

    PubMed

    Cammarota, Martín; Bevilaqua, Lia R; Rossato, Janine I; Lima, Ramón H; Medina, Jorge H; Izquierdo, Iván

    2008-07-29

    There is abundant literature on the role of the basolateral amygdala (BLA) and the CA1 region of the hippocampus in memory formation of inhibitory avoidance (IA) and other behaviorally arousing tasks. Here, we investigate molecular correlates of IA consolidation in the two structures and their relation to NMDA receptors (NMDArs) and beta-adrenergic receptors (beta-ADrs). The separate posttraining administration of antagonists of NMDAr and beta-ADr to BLA and CA1 is amnesic. IA training is followed by an increase of the phosphorylation of calcium and calmodulin-dependent protein kinase II (CaMKII) and ERK2 in CA1 but only an increase of the phosphorylation of ERK2 in BLA. The changes are blocked by NMDAr antagonists but not beta-ADr antagonists in CA1, and they are blocked by beta-ADr but not NMDAr antagonists in BLA. In addition, the changes are accompanied by increased phosphorylation of tyrosine hydroxylase in BLA but not in CA1, suggesting that beta-AD modulation results from local catecholamine synthesis in the former but not in the latter structure. NMDAr blockers in CA1 do not alter the learning-induced neurochemical changes in BLA, and beta-ADr blockade in BLA does not hinder those in CA1. When put together with other data from the literature, the present findings suggest that CA1 and BLA play a role in consolidation, but they operate to an extent in parallel, suggesting that each is probably involved with different aspects of the task studied.

  11. Chronic Stress Triggers Expression of Immediate Early Genes and Differentially Affects the Expression of AMPA and NMDA Subunits in Dorsal and Ventral Hippocampus of Rats

    PubMed Central

    Pacheco, Anibal; Aguayo, Felipe I.; Aliaga, Esteban; Muñoz, Mauricio; García-Rojo, Gonzalo; Olave, Felipe A.; Parra-Fiedler, Nicolas A.; García-Pérez, Alexandra; Tejos-Bravo, Macarena; Rojas, Paulina S.; Parra, Claudio S.; Fiedler, Jenny L.

    2017-01-01

    Previous studies in rats have demonstrated that chronic restraint stress triggers anhedonia, depressive-like behaviors, anxiety and a reduction in dendritic spine density in hippocampal neurons. In this study, we compared the effect of repeated stress on the expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptor subunits in dorsal and ventral hippocampus (VH). Adult male Sprague-Dawley rats were randomly divided into control and stressed groups, and were daily restrained in their motion (2.5 h/day) during 14 days. We found that chronic stress promotes an increase in c-Fos mRNA levels in both hippocampal areas, although it was observed a reduction in the immunoreactivity at pyramidal cell layer. Furthermore, Arc mRNAs levels were increased in both dorsal and VH, accompanied by an increase in Arc immunoreactivity in dendritic hippocampal layers. Furthermore, stress triggered a reduction in PSD-95 and NR1 protein levels in whole extract of dorsal and VH. Moreover, a reduction in NR2A/NR2B ratio was observed only in dorsal pole. In synaptosomal fractions, we detected a rise in NR1 in dorsal hippocampus (DH). By indirect immunofluorescence we found that NR1 subunits rise, especially in neuropil areas of dorsal, but not VH. In relation to AMPA receptor (AMPAR) subunits, chronic stress did not trigger any change, either in dorsal or ventral hippocampal areas. These data suggest that DH is more sensitive than VH to chronic stress exposure, mainly altering the expression of NMDA receptor (NMDAR) subunits, and probably favors changes in the configuration of this receptor that may influence the function of this area. PMID:28848384

  12. Chronic Stress Triggers Expression of Immediate Early Genes and Differentially Affects the Expression of AMPA and NMDA Subunits in Dorsal and Ventral Hippocampus of Rats.

    PubMed

    Pacheco, Anibal; Aguayo, Felipe I; Aliaga, Esteban; Muñoz, Mauricio; García-Rojo, Gonzalo; Olave, Felipe A; Parra-Fiedler, Nicolas A; García-Pérez, Alexandra; Tejos-Bravo, Macarena; Rojas, Paulina S; Parra, Claudio S; Fiedler, Jenny L

    2017-01-01

    Previous studies in rats have demonstrated that chronic restraint stress triggers anhedonia, depressive-like behaviors, anxiety and a reduction in dendritic spine density in hippocampal neurons. In this study, we compared the effect of repeated stress on the expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptor subunits in dorsal and ventral hippocampus (VH). Adult male Sprague-Dawley rats were randomly divided into control and stressed groups, and were daily restrained in their motion (2.5 h/day) during 14 days. We found that chronic stress promotes an increase in c-Fos mRNA levels in both hippocampal areas, although it was observed a reduction in the immunoreactivity at pyramidal cell layer. Furthermore, Arc mRNAs levels were increased in both dorsal and VH, accompanied by an increase in Arc immunoreactivity in dendritic hippocampal layers. Furthermore, stress triggered a reduction in PSD-95 and NR1 protein levels in whole extract of dorsal and VH. Moreover, a reduction in NR2A/NR2B ratio was observed only in dorsal pole. In synaptosomal fractions, we detected a rise in NR1 in dorsal hippocampus (DH). By indirect immunofluorescence we found that NR1 subunits rise, especially in neuropil areas of dorsal, but not VH. In relation to AMPA receptor (AMPAR) subunits, chronic stress did not trigger any change, either in dorsal or ventral hippocampal areas. These data suggest that DH is more sensitive than VH to chronic stress exposure, mainly altering the expression of NMDA receptor (NMDAR) subunits, and probably favors changes in the configuration of this receptor that may influence the function of this area.

  13. Dorsal hippocampal microinjection of chlorpheniramine reverses the anxiolytic-like effects of l-histidine and impairs emotional memory in mice.

    PubMed

    Canto-de-Souza, L; Garção, D C; Romaguera, F; Mattioli, R

    2015-02-05

    Several findings have pointed to the role of histaminergic neurotransmission in the modulation of anxiety-like behaviors and emotional memory. The elevated plus-maze (EPM) test has been widely used to investigate the process of anxiety and also has been used to investigate the process of learning and memory. Visual cues are relevant to the formation of spatial maps, and as the hippocampus is involved in this task, experiment 1 explored this issue. Experiment 2 investigated the effects of intraperitoneal (i.p.) injections of l-histidine (LH, a precursor of histamine) and of intra-dorsal hippocampus (intra-DH) injections of chlorpheniramine (CPA, an H1 receptor antagonist) on anxiety and emotional memory in mice re-exposed to the EPM. Mice received saline (SAL) or LH i.p. and SAL or CPA (0.016, 0.052, and 0.16 nmol/0.1 μl) intra-DH prior to Trial 1 (T1) and Trial 2 (T2). No significant changes were observed in the number of enclosed-arm entries (EAE) in T1, an EPM index of general exploratory activity. LH had an anxiolytic-like effect that was reversed by intra-DH injections of CPA. T2 versus T1 analysis revealed that only the lower dose of CPA resulted in impaired emotional memory. Combined injections of LH and CPA revealed that higher doses of CPA impair emotional memory. Taken together, these results suggest that LH and H1 receptors present in the dorsal hippocampus are involved in anxiety-related behaviors and emotional memory in mice submitted to EPM.

  14. Differential ability of the dorsal and ventral rat hippocampus to exhibit group I metabotropic glutamate receptor–dependent synaptic and intrinsic plasticity

    PubMed Central

    Tidball, Patrick; Burn, Hannah V.; Teh, Kai Lun; Volianskis, Arturas; Collingridge, Graham L.; Fitzjohn, Stephen M.

    2017-01-01

    Background The hippocampus is critically involved in learning and memory processes. Although once considered a relatively homogenous structure, it is now clear that the hippocampus can be divided along its longitudinal axis into functionally distinct domains, responsible for the encoding of different types of memory or behaviour. Although differences in extrinsic connectivity are likely to contribute to this functional differentiation, emerging evidence now suggests that cellular and molecular differences at the level of local hippocampal circuits may also play a role. Methods In this study, we have used extracellular field potential recordings to compare basal input/output function and group I metabotropic glutamate receptor-dependent forms of synaptic and intrinsic plasticity in area CA1 of slices taken from the dorsal and ventral sectors of the adult rat hippocampus. Results Using two extracellular electrodes to simultaneously record field EPSPs and population spikes, we show that dorsal and ventral hippocampal slices differ in their basal levels of excitatory synaptic transmission, paired-pulse facilitation, and EPSP-to-Spike coupling. Furthermore, we show that slices taken from the ventral hippocampus have a greater ability than their dorsal counterparts to exhibit long-term depression of synaptic transmission and EPSP-to-Spike potentiation induced by transient application of the group I mGluR agonist (RS)-3,5-dihydroxyphenylglycine. Conclusions Together, our results provide further evidence that the information processing properties of local hippocampal circuits differ in the dorsal and ventral hippocampal sectors, and that these differences may in turn contribute to the functional differentiation that exists along the hippocampal longitudinal axis.

  15. NK1 receptors antagonism of dorsal hippocampus counteract the anxiogenic-like effects induced by pilocarpine in non-convulsive Wistar rats.

    PubMed

    Duarte, Filipe Silveira; Hoeller, Alexandre Ademar; Duzzioni, Marcelo; Gavioli, Elaine Cristina; Canteras, Newton Sabino; De Lima, Thereza Christina Monteiro

    2014-05-15

    Recent evidence supports a role for the substance P (SP) in the control of anxiety and epilepsy disorders. Aversive stimuli alter SP levels and SP immunoreactivity in limbic regions, suggesting that changes in SP-NK1 receptor signaling may modulate the neuronal excitability involved in seizures and anxiogenesis. The involvement of NK1 receptors of the dorsal hippocampus and lateral septum in the anxiogenic-like effects induced by a single injection of pilocarpine (PILO) was examined in non-convulsive rats evaluated in the elevated plus-maze (EPM). Male Wistar rats were systemically injected with methyl-scopolamine (1mg/kg) followed 30 min later by saline or PILO (350 mg/kg) and only rats that did not present status epilepticus were used. One month later, vehicle or FK888 (100 pmol) - an NK1 receptor antagonist - were infused in the dorsal hippocampus or the lateral septum of the rats and then behaviorally evaluated in the EPM. Previous treatment with PILO decreased the time spent in and the frequency of entries in the open arms of the EPM, besides altering risk-assessment behaviors such as the number of unprotected head-dipping, protected stretch-attend postures and the frequency of open-arms end activity, showing thus a long-lasting anxiogenic-like profile. FK888 did not show any effect per se but inhibited the anxiogenic responses induced by PILO when injected into the dorsal hippocampus, but not into the lateral septum. Our data suggest that SP-NK1 receptor signaling of the dorsal hippocampus is involved in the anxiogenic-like profile induced by PILO in rats evaluated in the EPM test.

  16. Differential induction of c-Jun and Fos-like proteins in rat hippocampus and dorsal striatum after training in two water maze tasks.

    PubMed

    Teather, Lisa A; Packard, Mark G; Smith, Diane E; Ellis-Behnke, Rutledge G; Bazan, Nicolas G

    2005-09-01

    Research examining the neuroanatomical bases of memory in mammals suggests that the hippocampus and dorsal striatum are parts of independent memory systems that mediate "cognitive" and stimulus-response "habit" memory, respectively. At the molecular level, increasing evidence indicates a role for immediate early gene (IEG) expression in memory formation. The present experiment examined whether acquisition of cognitive and habit memory result in differential patterns of IEG protein product expression in these two brain structures. Adult male Long-Evans rats were trained in either a hippocampal-dependent spatial water maze task, or a dorsal striatal-dependent cued water maze task. Ninety minutes after task acquisition, brains were removed and processed for immunocytochemical procedures, and the number of cells expressing Fos-like immunoreactivity (Fos-like-IR) and c-Jun-IR in sections from the dorsal hippocampus and the dorsal striatum were counted. In the dorsal hippocampus of rats trained in the spatial task, there were significantly more c-Jun-IR pyramidal cells in the CA1 and CA3 regions, relative to rats that had acquired the cued task, yoked controls (free-swim), or naïve (home cage) rats. Relative to rats receiving cued task training and control conditions, increases in Fos-like IR were also observed in the CA1 region of rats trained in the spatial task. In rats that had acquired the cued task, patches of c-Jun-IR were observed in the posteroventral striatum; no such patches were evident in rats trained in the spatial task, yoked-control rats, or naïve rats. The results demonstrate that IEG protein product expression is up-regulated in a task-dependent and brain structure-specific manner shortly after acquisition of cognitive and habit memory tasks.

  17. Allopregnanolone microinjected into the lateral septum or dorsal hippocampus reduces immobility in the forced swim test: participation of the GABAA receptor.

    PubMed

    Rodríguez-Landa, Juan Francisco; Contreras, Carlos M; García-Ríos, Rosa Isela

    2009-10-01

    Allopregnanolone is a 5α-reduced metabolite of progesterone with actions on γ-aminobutyric acid-A (GABAA) receptors that produce antidepressant-like effects. However, little is known about the target brain regions that mediate its antidepressant-like effects. In this study, allopregnanolone (2.0 μg/0.3 μl/rat) or its vehicle (35% cyclodextrin solution) were microinjected into the lateral septum, septofimbrial, or dorsal hippocampus of male Wistar rats that had previously received intraperitoneal injections of either saline or the GABAA antagonist bicuculline (1.0 mg/kg), and its effects were evaluated in the open field and forced swim tests. Allopregnanolone microinjected into the lateral septum or dorsal hippocampus, but not septofimbrial nucleus, induced a longer latency to the first immobility and a shorter total immobility time in the forced swim test compared with vehicle. Bicuculline pretreatment reversed the effect of allopregnanolone. None of the treatments produced significant changes in crossings in the open field test. In conclusion, allopregnanolone produces an antidepressant-like effect in rats submitted to the forced swim test through actions on GABAA receptors located in the lateral septum and dorsal hippocampus, which is consistent with the antistress effect of GABAA agonists in these particular brain structures.

  18. Genetic disruption of the core circadian clock impairs hippocampus-dependent memory.

    PubMed

    Wardlaw, Sarah M; Phan, Trongha X; Saraf, Amit; Chen, Xuanmao; Storm, Daniel R

    2014-08-01

    Perturbing the circadian system by electrolytically lesioning the suprachiasmatic nucleus (SCN) or varying the environmental light:dark schedule impairs memory, suggesting that memory depends on the circadian system. We used a genetic approach to evaluate the role of the molecular clock in memory. Bmal1-/- mice, which are arrhythmic under constant conditions, were examined for hippocampus-dependent memory, LTP at the Schaffer-collateral synapse, and signal transduction activity in the hippocampus. Bmal1-/- mice exhibit impaired contextual fear and spatial memory. Furthermore, LTP in hippocampal slices from Bmal1-/- mice is also significantly decreased relative to that from wild-type mice. Activation of Erk1,2 MAP kinase (MAPK) during training for contextual fear memory and diurnal oscillation of MAPK activity and cAMP in the hippocampus is also lost in Bmal1-/- mice, suggesting that the memory defects are due to reduction of the memory consolidation pathway in the hippocampus. We conclude that critical signaling events in the hippocampus required for memory depend on BMAL1. © 2014 Wardlaw et al.; Published by Cold Spring Harbor Laboratory Press.

  19. Interaction between the dopaminergic and opioidergic systems in dorsal hippocampus in modulation of formalin-induced orofacial pain in rats.

    PubMed

    Reisi, Zahra; Haghparast, Amir; Pahlevani, Pouyan; Shamsizadeh, Ali; Haghparast, Abbas

    2014-09-01

    The hippocampus is a region of the brain that serves several functions. The dopaminergic system acts through D1- and D2-like receptors to interfere in pain modulation and the opioid receptors play major roles in analgesic processes and there are obvious overlaps between these two systems. The present study investigated the interaction between the opioidergic and dopaminergic systems in the dorsal hippocampus (CA1) region for formalin-induced orofacial pain. Two guide cannulae were stereotaxically implanted in the CA1 region and morphine (0.5, 1, 2 and 4 μg/0.5 μl saline) and naloxone (0.3, 1 and 3 μg/0.5 μl saline) were used as the opioid receptor agonist and antagonist, respectively. SKF-38393 (1 μg/0.5 μl saline) was used as a D1-like receptor agonist, quinpirole (2 μg/0.5 μl saline) as a D2-like receptor agonist, SCH-23390 (0.5 μg/0.5 μl saline) as a D1-like receptor antagonist and sulpiride (3 μg/0.5 μl DMSO) as a D2-like receptor antagonist. To induce orofacial pain, 50 μl of 1% formalin was subcutaneously injected into the left side of the upper lip. Our results showed that different doses of morphine significantly reduced orofacial pain in both phases induced by formalin. Naloxone (1 and 3 μg) reversed morphine induced analgesia in CA1. SKF-38393 and quinpirole with naloxone (1 μg) significantly decreased formalin-induced orofacial pain in both phases. SCH-23390 had no effect on the antinociceptive response of morphine in both phases of orofacial pain. Sulpiride reversed the antinociceptive effects of morphine only in the first phase, but this result was not significant. Our findings suggest that there is cross-talk between the opioidergic and dopaminergic systems. Opioidergic neurons also exerted antinociceptive effects by modulation of the dopaminergic system in the CA1 region of the brain.

  20. Transient Inactivation of the Neonatal Ventral Hippocampus Impairs Attentional Set-Shifting Behavior: Reversal with an α7 Nicotinic Agonist

    PubMed Central

    Brooks, Julie M; Pershing, Michelle L; Thomsen, Morten S; Mikkelsen, Jens D; Sarter, Martin; Bruno, John P

    2012-01-01

    Cognitive deficits represent a core symptom cluster in schizophrenia that are thought to reflect developmental dysregulations within a neural system involving the ventral hippocampus (VH), nucleus accumbens (NAC), and prefrontal cortex (PFC). The present experiments determined the cognitive effects of transiently inactivating VH in rats during a sensitive period of development. Neonatal (postnatal day 7, PD7) and adolescent (PD32) male rats received a single bilateral infusion of saline or tetrodotoxin (TTX) within the VH to transiently inactivate local circuitry and efferent outflow. Rats were tested as adults on an attentional set-shifting task. Performance in this task depends upon the integrity of the PFC and NAC. TTX infusions did not affect the initial acquisition or ability to learn an intra-dimensional shift. However, TTX rats required a greater number of trials than did controls to acquire the first reversal and extra-dimensional shift (ED) stages. These impairments were age and region-specific as rats infused with TTX into the VH at PD32, or into the dorsal hippocampus at PD7, exhibited performance in the task similar to that of controls. Finally, acute systemic administration of the partial α7 nicotinic acetylcholine receptor (nAChR) agonist SSR 180711 (3.0 mg/kg) eliminated the TTX-induced performance deficits. Given that patients with schizophrenia exhibit hippocampal pathophysiology and deficits in the ED stages of set-shifting tasks, our results support the significance of transient hippocampal inactivation as an animal model for studying the cognitive impairments in schizophrenia as well as the pro-cognitive therapeutic potential of α7 nAChR agonists. PMID:22781844

  1. Luteinizing hormone acts at the hippocampus to dampen spatial memory.

    PubMed

    Burnham, Veronica; Sundby, Christopher; Laman-Maharg, Abigail; Thornton, Janice

    2017-03-01

    Luteinizing hormone (LH) rises dramatically during and after menopause, and has been correlated with an increased incidence of Alzheimer's disease and decreased memory performance in humans and animal models. To test whether LH acts directly on the dorsal hippocampus to affect memory, ovariectomized female rats were infused with either the LH-homologue human chorionic gonadotropin (hCG) or the LH receptor antagonist deglycosylated-hCG (dg-hCG). Infusion of hCG into either the lateral ventricle or the dorsal hippocampus caused significant memory impairments in ovariectomized estradiol-treated females. Consistent with this, infusion of the LH antagonist dg-hCG into the dorsal hippocampus caused an amelioration of memory deficits in ovariectomized females. Furthermore, the gonadotropin-releasing hormone antagonist Antide, failed to act in the hippocampus to affect memory. These findings demonstrate a significant role for LH action in the dorsal hippocampus in spatial memory dysfunction. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Involvement of actin rearrangements within the amygdala and the dorsal hippocampus in aversive memories of drug withdrawal in acute morphine-dependent rats.

    PubMed

    Hou, Yuan-Yuan; Lu, Bin; Li, Mu; Liu, Yao; Chen, Jie; Chi, Zhi-Qiang; Liu, Jing-Gen

    2009-09-30

    Aversive memories of drug withdrawal can generate a motivational state leading to compulsive drug taking. Changes in synaptic plasticity may be involved in the formation of aversive memories. Dynamic rearrangement of the cytoskeletal actin, a major structural component of the dendritic spine, regulates synaptic plasticity. Here, the potential involvement of actin rearrangements in the induction of aversive memories of morphine withdrawal was examined. We found that lesions of the amygdala or dorsal hippocampus (DH) but not nucleus accumbens (NAc) impaired conditioned place aversion (CPA) of acute morphine-dependent rats. Accordingly, conditioned morphine withdrawal induced actin rearrangements in the amygdala and the DH but not in the NAc. In addition, we found that conditioned morphine withdrawal also increased activity-regulated cytoskeletal-associated protein (Arc) expression in the amygdala but not in the DH, although actin rearrangements were observed in both areas. We further found that inhibition of actin rearrangements by intra-amygdala or intra-DH injections of latrunculin A, an inhibitor of actin polymerization, significantly attenuated CPA. Furthermore, we found that manipulation of amygdala beta-adrenoceptor activity by its antagonist propranolol and agonist clenbuterol differentially altered actin rearrangements in the DH. Therefore, our findings reveal that actin rearrangements in the amygdala and the DH are required for the acquisition and consolidation of the aversive memories of drug withdrawal and that the beta-noradrenergic system within the amygdala modulates aversive memory consolidation by regulating actin rearrangements but not Arc protein expression in the DH, which is distinct from its role in modulation of inhibitory avoidance memory.

  3. Serotonin neuronal release from dorsal hippocampus following electrical stimulation of the dorsal and median raphé nuclei in conscious rats.

    PubMed

    Mokler, D J; Lariviere, D; Johnson, D W; Theriault, N L; Bronzino, J D; Dixon, M; Morgane, P J

    1998-01-01

    We have studied 5-hydroxytryptamine (5-HT) release in the hippocampal formation following electrical stimulation of the dorsal and median raphé nuclei in the behaving rat. The primary finding in this study is a decrease in neuronal release of serotonin in the dorsal hippocampal formation following electrical stimulation of either the dorsal or median raphé nucleus in conscious rats. At no time did electrical stimulation of either raphé nucleus result in behavioral, including vigilance state, changes. The amount of 5-HT released was found to be frequency dependent with higher frequencies (20 Hz) producing larger decreases in release of 5-HT. However, the pattern of release differs between the two raphé nuclei. Extracellular levels of 5-HT decrease during stimulation of the dorsal raphé, whereas levels decrease only following cessation of stimulation of the median raphé nucleus. This may relate to the patterns of innervation of the dorsal hippocampal formation by these two midbrain raphé nuclei and also may reflect an inhibition of median raphé cell firing during stimulation of the dorsal raphé. Electrical stimulation of the dorsal raphé in anesthetized animals resulted in an enhanced release of 5-HT. The suppression of 5-HT release in the dorsal hippocampal formation in behaving animals was long-lasting (over 2 h), suggesting that the control mechanisms that regulate 5-HT release operate over a long time-course. This difference in release between non-anesthetized and anesthetized animals may relate to anesthesia blocking long- and/or short-loop serotonin recurrent axonal collaterals negatively feeding back onto 5-HT1A and 5-HT1D somatodendritic autoreceptors on raphé neurons. Further, the anesthetized animal has diminished monoaminergic "gating" influences on the hippocampal formation, whereas the behaving animal is more complex with behavioral (vigilance) states associated with different patterns of gating of information flow through the hippocampal

  4. Differential expression of endocannabinoid system-related genes in the dorsal hippocampus following expression and reinstatement of morphine conditioned place preference in mice.

    PubMed

    Li, Wei; Zhang, Cong-Li; Qiu, Zheng-Guo

    2017-03-16

    The endocannabinoid signaling plays a critical role in mediating rewarding effects to morphine. The relative stability for the expression and reinstatement of morphine conditioned place preference (CPP) suggests the involvement of differential neuroadaptations in learned associations between environmental cues and morphine. Changes in gene expression in hippocampus through the endogenous cannabinoid system (eCB) may accompany and mediate the development of such neuroadaptations to repeated morphine stimulation. To test this possibility, we systematically compared the expression of eCB-related genes in the dorsal hippocampus following the expression, extinction, and reinstatement of morphine CPP using quantitative RT-PCR analyses. We found that expression of morphine CPP was associated with significant increases in mRNA expression for the primary clearance routes for anandamide (AEA) and 2-AG (fatty acid amide hydrolase [FAAH] and monoacylglycerol lipase [MAGL], respectively), but with reductions in cannabinoid 1 receptors (CB1R) and CB2R in dorsal hippocampus following the expression of CPP. However, our results indicated that decreased in MAGL and increased CB1R mRNA levels were accompanied with morphine CPP reinstatement. No significant changes in mRNA expression for enzymes involved in AEA and 2-AG biosynthesis (N-acylphosphatidylethanolamine phospholipase D [NAPEPLD] and diacylglycerol lipase-α/β [DAGLα/β], respectively) were found in all conditions. These results suggest that differential regulation of the synthesis and/or degradation of the eCB system contribute to the expression and reinstatement of morphine CPP.

  5. Activation of dopamine D1 receptors in the medial septum improves scopolamine-induced amnesia in the dorsal hippocampus.

    PubMed

    Zarrindast, Mohammad Reza; Ardjmand, Abolfazl; Ahmadi, Shamseddin; Rezayof, Ameneh

    2012-04-01

    In the present study, we investigated the influence of intra-medial septum (intra-MS) injections of dopamine D1 receptor agents on amnesia induced by intra-CA1 injections of a muscarinic acetylcholine receptor antagonist, scopolamine. This study used a step-through inhibitory (passive) avoidance task to assess memory in adult male Wistar rats. The results showed that in the animals that received post-training intra-MS injections of saline, intra-CA1 administrations of scopolamine (0.75, 1, and 2 μg/rat) decreased inhibitory avoidance (IA) memory consolidation as evidenced by a decrease in step-through latency on the test day, which was suggestive of drug-induced amnesia. Post-training intra-MS injections of a dopamine D1 receptor agonist, SKF38393 at doses of 0.1, 0.15, and 0.3 μg/rat had no effect, but at dose of 0.5 μg/rat impaired IA memory consolidation. Interestingly, intra-MS injections of SKF38393 (0.15, 0.3 and 0.5 μg/rat) significantly prevented amnesia induced by intra-CA1 injections of scopolamine (1 μg/rat). Intra-MS injections of a dopamine D1 receptor antagonist, SCH23390 (0.5 and 0.75 μg/rat) by itself impaired IA memory consolidation, and also at dose of 0.75 μg/rat increased amnesia induced by intra-CA1 administrations of an ineffective dose of scopolamine (0.5 μg/rat). Post-training intra-MS injections of ineffective doses of SCH23390 (0.1, 0.3 and 0.5 μg/rat) prevented an effective dose of SKF38393 response to the impaired effect of scopolamine. These results suggest that dopamine D1 receptors in the MS via projection neurons to the hippocampus affect impairment of memory consolidation induced by intra-CA injections of scopolamine.

  6. Impairment in Delayed Non-Matching to Sample Following Lesions of Dorsal Prefrontal Cortex

    PubMed Central

    Moore, Tara L; Schettler, Stephen P.; Killiany, Ronald J.; Rosene, Douglas L.; Moss, Mark B.

    2012-01-01

    The prefrontal cortex has been identified as essential for executive function, as well as for aspects of rule learning and recognition memory. As part of our studies to assess prefrontal cortical function in the monkey, we evaluated the effects of damage to the dorsal prefrontal cortex (DPFC) on the Category Set Shifting Task (CSST), a test of abstraction and set-shifting, and on the Delayed Non Matching-to-Sample (DNMS) task, a benchmark test of rule learning and recognition memory. The DPFC lesions in this study included dorsolateral and dorsomedial aspects of the PFC. In a previous report, we published evidence of an impairment on the CSST as a consequence of DPFC lesions (Moore et al, 2009). Here we report that monkeys with lesions of the DPFC were also markedly impaired relative to controls on both the acquisition (rule learning) and performance (recognition memory) conditions of trial-unique DNMS. The presence and extent of the deficits that we observed were of some surprise and support the possibility that the dorsal prefrontal cortex plays a more direct role in learning and recognition memory than had been previously thought. PMID:23088539

  7. Impairment in delayed nonmatching to sample following lesions of dorsal prefrontal cortex.

    PubMed

    Moore, Tara L; Schettler, Stephen P; Killiany, Ronald J; Rosene, Douglas L; Moss, Mark B

    2012-12-01

    The prefrontal cortex has been identified as essential for executive function, as well as for aspects of rule learning and recognition memory. As part of our studies to assess prefrontal cortical function in the monkey, we evaluated the effects of damage to the dorsal prefrontal cortex (DPFC) on the Category Set Shifting Task (CSST), a test of abstraction and set-shifting, and on the Delayed Nonmatching to Sample (DNMS) task, a benchmark test of rule learning and recognition memory. The DPFC lesions in this study included dorsolateral and dorsomedial aspects of the PFC. In a previous report, we published evidence of an impairment on the CSST as a consequence of DPFC lesions (Moore, Schettler, Killiany, Rosene, & Moss, 2009). Here we report that monkeys with lesions of the DPFC were also markedly impaired relative to controls on both the acquisition (rule learning) and performance (recognition memory) conditions of trial-unique DNMS. The presence and extent of the deficits that we observed were of some surprise and support the possibility that the dorsal prefrontal cortex plays a more direct role in learning and recognition memory than had been previously thought.

  8. Contribution of an SFK-Mediated Signaling Pathway in the Dorsal Hippocampus to Cocaine-Memory Reconsolidation in Rats.

    PubMed

    Wells, Audrey M; Xie, Xiaohu; Higginbotham, Jessica A; Arguello, Amy A; Healey, Kati L; Blanton, Megan; Fuchs, Rita A

    2016-02-01

    Environmentally induced relapse to cocaine seeking requires the retrieval of context-response-cocaine associative memories. These memories become labile when retrieved and must undergo reconsolidation into long-term memory storage to be maintained. Identification of the molecular underpinnings of cocaine-memory reconsolidation will likely facilitate the development of treatments that mitigate the impact of cocaine memories on relapse vulnerability. Here, we used the rat extinction-reinstatement procedure to test the hypothesis that the Src family of tyrosine kinases (SFK) in the dorsal hippocampus (DH) critically controls contextual cocaine-memory reconsolidation. To this end, we evaluated the effects of bilateral intra-DH microinfusions of the SFK inhibitor, PP2 (62.5 ng per 0.5 μl per hemisphere), following re-exposure to a cocaine-associated (cocaine-memory reactivation) or an unpaired context (no memory reactivation) on subsequent drug context-induced instrumental cocaine-seeking behavior. We also assessed alterations in the phosphorylation state of SFK targets, including GluN2A and GluN2B N-methyl-D-aspartate (NMDA) and GluA2 α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunits at the putative time of memory restabilization and following PP2 treatment. Finally, we evaluated the effects of intra-DH PEAQX (2.5 μg per 0.5 μl per hemisphere), a GluN2A-subunit-selective NMDAR antagonist, following, or in the absence of, cocaine-memory reactivation on subsequent drug context-induced cocaine-seeking behavior. GluN2A phosphorylation increased in the DH during putative memory restabilization, and intra-DH PP2 treatment inhibited this effect. Furthermore, PP2-as well as PEAQX-attenuated subsequent drug context-induced cocaine-seeking behavior, in a memory reactivation-dependent manner, relative to VEH. These findings suggest that hippocampal SFKs contribute to the long-term stability of cocaine-related memories that underlie contextual

  9. Contribution of an SFK-Mediated Signaling Pathway in the Dorsal Hippocampus to Cocaine-Memory Reconsolidation in Rats

    PubMed Central

    Wells, Audrey M; Xie, Xiaohu; Higginbotham, Jessica A; Arguello, Amy A; Healey, Kati L; Blanton, Megan; Fuchs, Rita A

    2016-01-01

    Environmentally induced relapse to cocaine seeking requires the retrieval of context–response–cocaine associative memories. These memories become labile when retrieved and must undergo reconsolidation into long-term memory storage to be maintained. Identification of the molecular underpinnings of cocaine-memory reconsolidation will likely facilitate the development of treatments that mitigate the impact of cocaine memories on relapse vulnerability. Here, we used the rat extinction-reinstatement procedure to test the hypothesis that the Src family of tyrosine kinases (SFK) in the dorsal hippocampus (DH) critically controls contextual cocaine-memory reconsolidation. To this end, we evaluated the effects of bilateral intra-DH microinfusions of the SFK inhibitor, PP2 (62.5 ng per 0.5 μl per hemisphere), following re-exposure to a cocaine-associated (cocaine-memory reactivation) or an unpaired context (no memory reactivation) on subsequent drug context-induced instrumental cocaine-seeking behavior. We also assessed alterations in the phosphorylation state of SFK targets, including GluN2A and GluN2B N-methyl-D-aspartate (NMDA) and GluA2 α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunits at the putative time of memory restabilization and following PP2 treatment. Finally, we evaluated the effects of intra-DH PEAQX (2.5 μg per 0.5 μl per hemisphere), a GluN2A-subunit-selective NMDAR antagonist, following, or in the absence of, cocaine-memory reactivation on subsequent drug context-induced cocaine-seeking behavior. GluN2A phosphorylation increased in the DH during putative memory restabilization, and intra-DH PP2 treatment inhibited this effect. Furthermore, PP2—as well as PEAQX—attenuated subsequent drug context-induced cocaine-seeking behavior, in a memory reactivation-dependent manner, relative to VEH. These findings suggest that hippocampal SFKs contribute to the long-term stability of cocaine-related memories that underlie

  10. Dorsal hippocampus cannabinoid type 1 receptors modulate the expression of contextual fear conditioning in rats: Involvement of local glutamatergic/nitrergic and GABAergic neurotransmissions.

    PubMed

    Spiacci, Gabriela B L; Antero, Leandro S; Reis, Daniel G; Lisboa, Sabrina F; Resstel, Leonardo B

    2016-10-01

    The cannabinoid receptor type 1 (CB1) is highly expressed in the dorsal portion of hippocampus - a brain region that has been involved in the control of conditioned emotional response (CER) in the contextual fear conditioning (CFC) model. These responses are characterized by increased freezing behavior and autonomic parameters. Moreover, CB1 receptors activation negatively modulate the release of several neurotransmitters, including glutamate and GABA, which also have been related to modulation of CER. Therefore, our aim was to investigate the involvement of CB1 receptors in the dorsal hippocampus on CER expression. Independent groups of male Wistar rats submitted to the contextual fear conditioning received bilateral intra-hippocampal injections (500 nL/side) of the following drugs or vehicle before re-exposure to the aversive context: AM251 (CB1 antagonist; 0.1, 0.3 and 1nmol); AP7 (NMDA antagonist; 1nmol)+AM251 (0.3nmol); NPLA (0.01nmol; nNOS inhibitor)+AM251 (0.3nmol); Bicuculline (1.3pmol; GABAA antagonist)+AM251 (0.1 and 1nmol). In the present paper, AM251 (0.3nmol) increased CER, while this response was prevented by both AP7 and NPLA pretreatment. After pretreatment with Bicuculline, the lower and higher ineffective doses of AM251 were able to increase the CER, supporting the balance between GABAergic and glutamatergic mechanisms controlling this response. Our results suggest that increased CER evoked by CB1 blockade in the dorsal hippocampus depends on NMDA receptor activation and NO formation. Moreover, a fine-tune control promoted by GABAergic and glutamatergic mechanisms in this brain area modulate the CER after CB1 blockade. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

  11. Subregional Structural Alterations in Hippocampus and Nucleus Accumbens Correlate with the Clinical Impairment in Patients with Alzheimer's Disease Clinical Spectrum: Parallel Combining Volume and Vertex-Based Approach.

    PubMed

    Nie, Xiuling; Sun, Yu; Wan, Suiren; Zhao, Hui; Liu, Renyuan; Li, Xueping; Wu, Sichu; Nedelska, Zuzana; Hort, Jakub; Qing, Zhao; Xu, Yun; Zhang, Bing

    2017-01-01

    Deep gray matter structures are associated with memory and other important functions that are impaired in Alzheimer's disease (AD) and mild cognitive impairment (MCI). However, systematic characterization of the subregional atrophy and deformations in these structures in AD and MCI still need more investigations. In this article, we combined complex volumetry- and vertex-based analysis to investigate the pattern of subregional structural alterations in deep gray matter structures and its association with global clinical scores in AD (n = 30) and MCI patients (n = 30), compared to normal controls (NCs, n = 30). Among all seven pairs of structures, the bilateral hippocampi and nucleus accumbens showed significant atrophy in AD compared with NCs (p < 0.05). But only the subregional atrophy in the dorsal-medial part of the left hippocampus, the ventral part of right hippocampus, and the left nucleus accumbens, the posterior part of the right nucleus accumbens correlated with the worse clinical scores of MMSE and MOCA (p < 0.05). Furthermore, the medial-ventral part of right thalamus significantly shrank and correlated with clinical scores without decreasing in its whole volume (p > 0.05). In conclusion, the atrophy of these four subregions in bilateral hippocampi and nucleus accumbens was associated with cognitive impairment of patients, which might be potential target regions of treatment in AD. The surface analysis could provide additional information to volume comparison in finding the early pathological progress in deep gray matter structures.

  12. Blockade of dorsal hippocampal orexin-1 receptors impaired morphine-induced state-dependent learning.

    PubMed

    Farahmandfar, Maryam; Kadivar, Mehdi; Rastipisheh, Sareh

    2016-12-01

    Behavioral abnormalities associated with opiate addiction include memory and learning deficits, which are the result of some alterations in the neuromodulatory systems. Recently, orexin has shown to influence drug addiction neural circuitry, specifically in mediating reward-related perception and memory. To explore the possible interaction of orexinergic and opioidergic system on modulation of learning and memory, we have investigated the effects of intra-dorsal hippocampal (intra-CA1) administration of orexin-1 receptor agonist and the competitive orexin-1 antagonist, SB-334867, on morphine-induced memory impairment by using step-down passive avoidance task in mice. Pre-training injection of morphine (5mg/kg, i.p.) impaired memory, which was restored when 24h later the same dose of the drug was administered. Pre-test administration of orexin-1 (0.5, 5 and 50pmol, intra-CA1) had not a significant effect on the retention latency compared to the saline-treated animals, but it restored the memory impairment induced by pre-training morphine (5mg/kg, i.p.). Pre-test administration of SB-334867 (10, 20 and 40nmol, intra-CA1) by itself decreased the retention latencies of passive avoidance task. Co-administration of orexin-1 (0.5, 5 and 50pmol, intra-CA1) and morphine (1mg/kg, i.p.) on the test day induced morphine state-dependent memory. Conversely, pre-test injection of SB-334867 (10, 20 and 40nmol, intra-CA1) inhibited the orexin-1-induced potentiation of morphine state-dependent learning on the test day. It is concluded that dorsal hippocampal orexin-1 receptors may be involved, at least in part, in morphine state-dependent learning in mice. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. Impaired familiarity with preserved recollection after anterior temporal-lobe resection that spares the hippocampus

    PubMed Central

    Bowles, Ben; Crupi, Carina; Mirsattari, Seyed M.; Pigott, Susan E.; Parrent, Andrew G.; Pruessner, Jens C.; Yonelinas, Andrew P.; Köhler, Stefan

    2007-01-01

    It is well established that the medial-temporal lobe (MTL) is critical for recognition memory. The MTL is known to be composed of distinct structures that are organized in a hierarchical manner. At present, it remains controversial whether lower structures in this hierarchy, such as perirhinal cortex, support memory functions that are distinct from those of higher structures, in particular the hippocampus. Perirhinal cortex has been proposed to play a specific role in the assessment of familiarity during recognition, which can be distinguished from the selective contributions of the hippocampus to the recollection of episodic detail. Some researchers have argued, however, that the distinction between familiarity and recollection cannot capture functional specialization within the MTL and have proposed single-process accounts. Evidence supporting the dual-process view comes from demonstrations that selective hippocampal damage can produce isolated recollection impairments. It is unclear, however, whether temporal-lobe lesions that spare the hippocampus can produce selective familiarity impairments. Without this demonstration, single-process accounts cannot be ruled out. We examined recognition memory in NB, an individual who underwent surgical resection of left anterior temporal-lobe structures for treatment of intractable epilepsy. Her resection included a large portion of perirhinal cortex but spared the hippocampus. The results of four experiments based on three different experimental procedures (remember-know paradigm, receiver operating characteristics, and response-deadline procedure) indicate that NB exhibits impaired familiarity with preserved recollection. The present findings thus provide a crucial missing piece of support for functional specialization in the MTL. PMID:17905870

  14. Sleep deprivation impairs spatial memory and decreases extracellular signal-regulated kinase phosphorylation in the hippocampus.

    PubMed

    Guan, Zhiwei; Peng, Xuwen; Fang, Jidong

    2004-08-20

    Loss of sleep may result in memory impairment. However, little is known about the biochemical basis for memory deficits induced by sleep deprivation. Extracellular signal-regulated kinase (ERK) is involved in memory consolidation in different tasks. Phosphorylation of ERK is necessary for its activation and is an important step in mediating neuronal responses to synaptic activities. The aim of the present study was to determine the effects of total sleep deprivation (TSD) on memory and ERK phosphorylation in the brain. Rats were trained in Morris water maze to find a hidden platform (a spatial task) or a visible platform (a nonspatial task) after 6 h TSD or spontaneous sleep. TSD had no effect on spatial learning, but significantly impaired spatial memory tested 24 h after training. Nonspatial learning and memory were not impaired by TSD. Phospho-ERK levels in the hippocampus were significantly reduced after 6 h TSD compared to the controls and returned to the control levels after 2 h recovery sleep. Total ERK1 and ERK2 were slightly increased after 6 h TSD and returned to the control levels after 2 h recovery sleep. These alterations were not observed in the cortex after TSD. Protein phosphotase-1 and mitogen-activated protein kinase phosphatase-2, which dephosphorylates phospho-ERK, were also measured, but they were not altered by TSD. The impairments of both spatial memory and ERK phosphorylation indicate that the hippocampus is vulnerable to sleep loss. These results are consistent with the idea that decreased ERK activation in the hippocampus is involved in sleep deprivation-induced spatial memory impairment.

  15. Learning impairment caused by a toxin produced by Pfiesteria piscicida infused into the hippocampus of rats.

    PubMed

    Levin, Edward D; Blackwelder, W Paul; Glasgow, Howard B; Burkholder, JoAnn M; Moeller, Peter D R; Ramsdell, John S

    2003-01-01

    Pfiesteria piscicida, an estuarine dinoflagellate, which has been shown to kill fish, has also been associated with neurocognitive deficits in humans. With a rat model, we have demonstrated the cause-and-effect relationship between Pfiesteria exposure and learning impairment. In several studies, we have replicated the finding in Sprague-Dawley rats that exposure to fixed acute doses of Pfiesteria cells or filtrates caused radial-arm maze learning impairment. Recently, this finding of Pfiesteria-induced learning impairment in rats has been independently replicated in another laboratory as well. We have demonstrated significant Pfiesteria-induced learning impairment in both the win-shift and repeated-acquisition tasks in the radial-arm maze and in reversal learning in a visual operant signal detection task. These learning impairments have been seen as long as 10 weeks after a single acute exposure to Pfiesteria. In the current study, we used a hydrophilic toxin isolated from clonal P. piscicida cultures (PfTx) and tested its effect when applied locally to the ventral hippocampus on repeated acquisition of rats in the radial-arm maze. Toxin exposure impaired choice accuracy in the radial-arm maze repeated acquisition procedure. The PfTx-induced impairment was seen at the beginning of the session and the early learning deficit was persistent across 6 weeks of testing after a single administration of the toxin. Eventually, with enough practice, in each session, the PfTx-exposed rats did learn that session's problem as did control rats. This model has demonstrated the cause-and-effect relationship between exposure to a hydrophilic toxin produced by P. piscicida and learning impairment, and specifically that the ventral hippocampus was critically involved.

  16. Structural impairments of hippocampus in coal mine gas explosion-related posttraumatic stress disorder.

    PubMed

    Zhang, Quan; Zhuo, Chuanjun; Lang, Xu; Li, Huabing; Qin, Wen; Yu, Chunshui

    2014-01-01

    Investigations on hippocampal and amygdalar volume have revealed inconsistent results in patients with posttraumatic stress disorder (PTSD). Little is known about the structural covariance alterations between the hippocampus and amygdala in PTSD. In this study, we evaluated the alteration in the hippocampal and amygdalar volume and their structural covariance in the coal mine gas explosion related PTSD. High resolution T1-weighted magnetic resonance imaging (MRI) was performed on coal mine gas explosion related PTSD male patients (n = 14) and non-traumatized coalminers without PTSD (n = 25). The voxel-based morphometry (VBM) method was used to test the inter-group differences in hippocampal and amygdalar volume as well as the inter-group differences in structural covariance between the ipsilateral hippocampus and amygdala. PTSD patients exhibited decreased gray matter volume (GMV) in the bilateral hippocampi compared to controls (p<0.05, FDR corrected). GMV covariances between the ipsilateral hippocampus and amygdala were significantly reduced in PTSD patients compared with controls (p<0.05, FDR corrected). The coalminers with gas explosion related PTSD had decreased hippocampal volume and structural covariance with the ipsilateral amygdala, suggesting that the structural impairment of the hippocampus may implicate in the pathophysiology of PTSD.

  17. Dorsal versus ventral hippocampal contributions to trace and contextual conditioning: differential effects of regionally selective NMDA receptor antagonism on acquisition and expression.

    PubMed

    Czerniawski, Jennifer; Ree, Fredrick; Chia, Chester; Otto, Tim

    2012-07-01

    The dorsal and ventral subregions of the hippocampus likely play dissociable roles in some forms of learning. For example, we have previously demonstrated that temporary inactivation of ventral, but not dorsal, hippocampus dramatically impaired the acquisition of trace fear conditioning, while temporary inactivation of dorsal, but not ventral, hippocampus impaired spatially guided reinforced alternation (Czerniawski et al. (2009) Hippocampus 19:20-32). Importantly, emerging data suggest that lesions, temporary inactivation, and NMDA receptor antagonism within these subregions can produce quite different patterns of behavioral effects when administered into the same region. Specifically, while neither lesions nor temporary inactivation of dorsal hippocampus impair the acquisition of trace fear conditioning, learning in this paradigm is severely impaired by pre-training administration of the NMDA receptor antagonist dl-2-phosphonovaleric acid (APV) in dorsal hippocampus; the effect of NMDA receptor antagonism within ventral hippocampus on the acquisition and expression of trace conditioning, or on learning in general, has not yet been systematically explored. The present study extends our previous work examining the differential effect of lesions or inactivation of the dorsal and ventral hippocampal subregions by systematically examining the effect of regionally selective pre-training or pre-testing administration of APV on the acquisition and expression of trace and contextual fear conditioning. The results of these studies demonstrate that while pre-training NMDA receptor antagonism within either the dorsal or ventral subregion of the hippocampus impaired the acquisition of both trace and contextual conditioning, pre-testing NMDA receptor antagonism within ventral, but not dorsal, hippocampus impaired the expression of previously-acquired trace and contextual fear conditioning. These data suggest that selectively manipulating the integrity of individual subregions

  18. Stress induced a shift from dorsal hippocampus to prefrontal cortex dependent memory retrieval: role of regional corticosterone

    PubMed Central

    Dominguez, Gaelle; Faucher, Pierre; Henkous, Nadia; Krazem, Ali; Piérard, Christophe; Béracochéa, Daniel

    2014-01-01

    Most of the deleterious effects of stress on memory retrieval are due to a dysfunction of the hippocampo-prefrontal cortex interplay. The role of the stress-induced regional corticosterone increase in such dysfunction remains however unclear, since there is no published study as yet dedicated to measuring corticosterone concentrations simultaneously in both the prefrontal cortex (mPFC) and the hippocampus (dHPC) in relation with memory impairments. To that aim, we first showed in Experiment 1 that an acute stress (3 electric footschocks; 0.9 mA each) delivered before memory testing reversed the memory retrieval pattern (MRP) in a serial discrimination task in which mice learned two successive discriminations. More precisely, whereas non-stressed animals remembered accurately the first learned discrimination and not the second one, stressed mice remembered more accurately the second discrimination but not the first one. We demonstrated that local inactivation of dHPC or mPFC with the anesthetic lidocaine recruited the dHPC activity in non-stress conditions whereas the stress-induced MRP inversion recruited the mPFC activity. In a second experiment, we showed that acute stress induced a very similar time-course evolution of corticosterone rises within both the mPFC and dHPC. In a 3rd experiment, we found however that in situ injections of corticosterone either within the mPFC or the dHPC before memory testing favored the emergence of the mPFC-dependent MRP but blocked the emergence of the dHPC-dependent one. Overall, our study evidences that the simultaneous increase of corticosterone after stress in both areas induces a shift from dHPC (non-stress condition) to mPFC-dependent MRP and that corticosterone is critically involved in mediating the deleterious effects of stress on cognitive functions involving the mPFC-HPC interplay. PMID:24860451

  19. Stress induced a shift from dorsal hippocampus to prefrontal cortex dependent memory retrieval: role of regional corticosterone.

    PubMed

    Dominguez, Gaelle; Faucher, Pierre; Henkous, Nadia; Krazem, Ali; Piérard, Christophe; Béracochéa, Daniel

    2014-01-01

    Most of the deleterious effects of stress on memory retrieval are due to a dysfunction of the hippocampo-prefrontal cortex interplay. The role of the stress-induced regional corticosterone increase in such dysfunction remains however unclear, since there is no published study as yet dedicated to measuring corticosterone concentrations simultaneously in both the prefrontal cortex (mPFC) and the hippocampus (dHPC) in relation with memory impairments. To that aim, we first showed in Experiment 1 that an acute stress (3 electric footschocks; 0.9 mA each) delivered before memory testing reversed the memory retrieval pattern (MRP) in a serial discrimination task in which mice learned two successive discriminations. More precisely, whereas non-stressed animals remembered accurately the first learned discrimination and not the second one, stressed mice remembered more accurately the second discrimination but not the first one. We demonstrated that local inactivation of dHPC or mPFC with the anesthetic lidocaine recruited the dHPC activity in non-stress conditions whereas the stress-induced MRP inversion recruited the mPFC activity. In a second experiment, we showed that acute stress induced a very similar time-course evolution of corticosterone rises within both the mPFC and dHPC. In a 3rd experiment, we found however that in situ injections of corticosterone either within the mPFC or the dHPC before memory testing favored the emergence of the mPFC-dependent MRP but blocked the emergence of the dHPC-dependent one. Overall, our study evidences that the simultaneous increase of corticosterone after stress in both areas induces a shift from dHPC (non-stress condition) to mPFC-dependent MRP and that corticosterone is critically involved in mediating the deleterious effects of stress on cognitive functions involving the mPFC-HPC interplay.

  20. Dorsal root ganglionopathy is responsible for the sensory impairment in CANVAS

    PubMed Central

    McLean, Catriona A.; Rodriguez, Michael L.; Chancellor, Andrew M.; Mossman, Stuart; Lamont, Duncan; Roberts, Leslie; Storey, Elsdon; Halmagyi, G. Michael

    2014-01-01

    Objective: To elucidate the neuropathology in cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS), a novel cerebellar ataxia comprised of the triad of cerebellar impairment, bilateral vestibular hypofunction, and a peripheral sensory deficit. Method: Brain and spinal neuropathology in 2 patients with CANVAS, together with brain and otopathology in another patient with CANVAS, were examined postmortem. Results: Spinal cord pathology demonstrated a marked dorsal root ganglionopathy with secondary tract degeneration. Cerebellar pathology showed loss of Purkinje cells, predominantly in the vermis. Conclusion: The likely underlying sensory pathology in CANVAS is loss of neurons from the dorsal root and V, VII, and VIII cranial nerve ganglia—in other words, it is a “neuronopathy” rather than a “neuropathy.” Clinically, CANVAS is a differential diagnosis for both spinocerebellar ataxia type 3 (or Machado-Joseph disease) and Friedreich ataxia. In addition, there are 6 sets of sibling pairs, implying that CANVAS is likely to be a late-onset recessive or autosomal dominant with reduced penetrance disorder, and identification of the culprit gene is currently a target of investigation. PMID:24682971

  1. The progesterone-induced enhancement of object recognition memory consolidation involves activation of the extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin (mTOR) pathways in the dorsal hippocampus.

    PubMed

    Orr, Patrick T; Rubin, Amanda J; Fan, Lu; Kent, Brianne A; Frick, Karyn M

    2012-04-01

    Although much recent work has elucidated the biochemical mechanisms underlying the modulation of memory by 17β-estradiol, little is known about the signaling events through which progesterone (P) regulates memory. We recently demonstrated that immediate post-training infusion of P into the dorsal hippocampus enhances object recognition memory consolidation in young ovariectomized female mice (Orr et al., 2009). The goal of the present study was to identify the biochemical alterations that might underlie this mnemonic enhancement. We hypothesized that the P-induced enhancement of object recognition would be dependent on activation of the ERK and mTOR pathways. In young ovariectomized mice, we found that bilateral dorsal hippocampal infusion of P significantly increased levels of phospho-p42 ERK and the mTOR substrate S6K in the dorsal hippocampus 5 min after infusion. Phospho-p42 ERK levels were downregulated 15 min after infusion and returned to baseline 30 min after infusion, suggesting a biphasic effect of P on ERK activation. Dorsal hippocampal ERK and mTOR activation were necessary for P to facilitate memory consolidation, as suggested by the fact that inhibitors of both pathways infused into the dorsal hippocampus immediately after training blocked the P-induced enhancement of object recognition. Collectively, these data provide the first demonstration that the ability of P to enhance memory consolidation depends on the rapid activation of cell signaling and protein synthesis pathways in the dorsal hippocampus.

  2. Direct Electrical Stimulation of the Human Entorhinal Region and Hippocampus Impairs Memory.

    PubMed

    Jacobs, Joshua; Miller, Jonathan; Lee, Sang Ah; Coffey, Tom; Watrous, Andrew J; Sperling, Michael R; Sharan, Ashwini; Worrell, Gregory; Berry, Brent; Lega, Bradley; Jobst, Barbara C; Davis, Kathryn; Gross, Robert E; Sheth, Sameer A; Ezzyat, Youssef; Das, Sandhitsu R; Stein, Joel; Gorniak, Richard; Kahana, Michael J; Rizzuto, Daniel S

    2016-12-07

    Deep brain stimulation (DBS) has shown promise for treating a range of brain disorders and neurological conditions. One recent study showed that DBS in the entorhinal region improved the accuracy of human spatial memory. Based on this line of work, we performed a series of experiments to more fully characterize the effects of DBS in the medial temporal lobe on human memory. Neurosurgical patients with implanted electrodes performed spatial and verbal-episodic memory tasks. During the encoding periods of both tasks, subjects received electrical stimulation at 50 Hz. In contrast to earlier work, electrical stimulation impaired memory performance significantly in both spatial and verbal tasks. Stimulation in both the entorhinal region and hippocampus caused decreased memory performance. These findings indicate that the entorhinal region and hippocampus are causally involved in human memory and suggest that refined methods are needed to use DBS in these regions to improve memory. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Impairment of synaptic development in the hippocampus of diabetic Goto-Kakizaki rats.

    PubMed

    Matsunaga, Yuki; Negishi, Takayuki; Hatakeyama, Akinori; Kawagoe, Yuta; Sawano, Erika; Tashiro, Tomoko

    2016-10-01

    Insulin receptor signaling has been shown to regulate essential aspects of CNS function such as synaptic plasticity and neuronal survival. To elucidate its roles during CNS development in vivo, we examined the synaptic and cognitive development of the spontaneously diabetic Goto-Kakizaki (GK) rats in the present study. GK rats are non-obese models of type 2 diabetes established by selective inbreeding of Wistar rats based on impaired glucose tolerance. Though they start exhibiting only moderate hyperglycemia without changes in plasma insulin levels from 3 weeks postnatally, behavioral alterations in the open-field as well as significant impairments in memory retention compared with Wistar rats were observed at 10 weeks and were worsened at 20 weeks. Alterations in insulin receptor signaling and signs of insulin resistance were detected in the GK rat hippocampus at 3 weeks, as early as in other insulin-responsive peripheral tissues. Significant reduction of an excitatory postsynaptic scaffold protein, PSD95, was found at 5w and later in the hippocampus of GK rats due to the absence of a two-fold developmental increase of this protein observed in Wistar control rats between 3 and 20w. In the GK rat hippocampus, NR2A which is a NMDA receptor subunit selectively anchored to PSD95 was also reduced. In contrast, both NR2B and its anchoring protein, SAP102, showed similar developmental profiles in Wistar and GK rats with expression peaks at 2 and 3w. The results suggest that early alterations in insulin receptor signaling in the GK rat hippocampus may affect cognitive performance by suppressing synaptic maturation.

  4. Lesions to the CA2 region of the hippocampus impair social memory in mice

    PubMed Central

    Stevenson, Erica L.; Caldwell, Heather K.

    2014-01-01

    The function of the CA2 region of the hippocampus is poorly understood. While the CA1 and CA3 regions have been extensively studied, for years the CA2 region has primarily been viewed as a linking area between the two. However, the CA2 region is known to have distinct neurochemical and structural features that are different from the other parts of hippocampus and in recent years it has been suggested that the CA2 region may play a role in the formation and or recall of olfactory-based memories needed for normal social behavior. While this hypothesis has been supported by hippocampal lesion studies that have included the CA2 region, no studies have attempted to specifically lesion the CA2 region of the hippocampus in mice to determine the effects on social recognition memory and olfaction. To fill this knowledge gap, we sought to perform excitotoxic N-methyl-D aspartate (NMDA) lesions of the CA2 region in mice and determine the effects on social recognition memory. We predicted that lesions of the CA2 region would impair social recognition memory. We then went on to test olfaction in CA2 lesioned mice since social memory requires a functional olfactory system. Consistent with our prediction, we found that CA2 lesioned animals have impaired social recognition. These findings are significant because they confirm that the CA2 region of the hippocampus is a part of the neural circuitry that regulates social recognition memory, which may have implications for our understanding of the neural regulation of social behavior across species. PMID:25131412

  5. Region-specific roles of the prelimbic cortex, the dorsal CA1, the ventral DG and ventral CA1 of the hippocampus in the fear return evoked by a sub-conditioning procedure in rats.

    PubMed

    Fu, Juan; Xing, Xiaoli; Han, Mengfi; Xu, Na; Piao, Chengji; Zhang, Yue; Zheng, Xigeng

    2016-02-01

    The return of learned fear is an important issue in anxiety disorder research since an analogous process may contribute to long-term fear maintenance or clinical relapse. A number of studies demonstrate that mPFC and hippocampus are important in the modulation of post-extinction re-expression of fear memory. However, the region-specific role of these structures in the fear return evoked by a sub-threshold conditioning (SC) is not known. In the present experiments, we first examined specific roles of the prelimbic cortex (PL), the dorsal hippocampus (DH, the dorsal CA1 area in particular), the ventral hippocampus (the ventral dentate gyrus (vDG) and the ventral CA1 area in particular) in this fear return process. Then we examined the role of connections between PL and vCA1 with this behavioral approach. Rats were subjected to five tone-shock pairings (1.0-mA shock) to induce conditioned fear (freezing), followed by three fear extinction sessions (25 tone-alone trials each session). After a post-test for extinction memory, some rats were retrained with the SC procedure to reinstate tone-evoked freezing. Rat groups were injected with low doses of the GABAA agonist muscimol to selectively inactivate PL, DH, vDG, or vCA1 120 min before the fear return test. A disconnection paradigm with ipsilateral or contralateral muscimol injection of the PL and the vCA1 was used to examine the role of this pathway in the fear return. We found that transient inactivation of these areas significantly impaired fear return (freezing): inactivation of the prelimbic cortex blocked SC-evoked fear return in particular but did not influence fear expression in general; inactivation of the DH area impaired fear return, but had no effect on the extinction retrieval process; both ventral DG and ventral CA1 are required for the return of extinguished fear whereas only ventral DG is required for the extinction retrieval. These findings suggest that PL, DH, vDG, and vCA1 all contribute to the fear

  6. Onset of hippocampus-dependent memory impairments in 5XFAD transgenic mouse model of Alzheimer's disease.

    PubMed

    Girard, Stéphane D; Jacquet, Marlyse; Baranger, Kévin; Migliorati, Martine; Escoffier, Guy; Bernard, Anne; Khrestchatisky, Michel; Féron, François; Rivera, Santiago; Roman, François S; Marchetti, Evelyne

    2014-07-01

    The 5XFAD mice are an early-onset transgenic model of Alzheimer's disease (AD) in which amyloid plaques are first observed between two and four months of age in the cortical layer five and in the subiculum of the hippocampal formation. Although cognitive alterations have been described in these mice, there are no studies that focused on the onset of hippocampus-dependent memory deficits, which are a hallmark of the prodromal stage of AD. To identify when the first learning and memory impairments appear, 5XFAD mice of two, four, and six months of age were compared with their respective wild-type littermates using the olfactory tubing maze, which is a very sensitive hippocampal-dependent task. Deficits in learning and memory started at four months with a substantial increase at six months of age while no olfactory impairments were observed. The volumetric study using magnetic resonance imaging of the whole brain and specific areas (olfactory bulb, striatum, and hippocampus) did not reveal neuro-anatomical difference. Slight memory deficits appeared at 4 months of age in correlation with an increased astrogliosis and amyloid plaque formation. This early impairment in learning and memory related to the hippocampal dysfunction is particularly suited to assess preclinical therapeutic strategies aiming to delay or suppress the onset of AD. © 2014 Wiley Periodicals, Inc.

  7. Liquiritigenin ameliorates memory and cognitive impairment through cholinergic and BDNF pathways in the mouse hippocampus.

    PubMed

    Ko, Yong-Hyun; Kwon, Seung-Hwan; Lee, Seok-Yong; Jang, Choon-Gon

    2017-09-22

    Liquiritigenin (LQ), a flavonoid extracted from the radix of Glycyrrhiza, has anti-inflammatory and neuroprotective properties. In this study, we evaluated the cognitive enhancing effects of LQ on learning and memory impairments induced by scopolamine (0.5 mg/kg, i.p.), a muscarinic antagonist, using the Y-maze, passive avoidance, and novel object recognition tests. A single administration of LQ significantly improved scopolamine-induced cognitive impairments in these behavioral tests. In addition, LQ dramatically inhibited acetylcholinesterase and thiobarbituric acid reactive substance activities in the hippocampus of scopolamine-induced mice in a dose-dependent manner. Furthermore, LQ markedly increased the protein level of brain-derived neurotrophic factor (BDNF) and phosphorylation of extracellular signal-regulated kinase (ERK) and cAMP response element binding (CREB) in the hippocampus of scopolamine-induced mice. Taken together, our results indicate that LQ may be useful for the treatment of learning and memory impairments, and that the beneficial effects of LQ are mediated, in part, by cholinergic and BDNF/ERK/CREB signaling enhancement and/or protection.

  8. NMDA receptors of dorsal hippocampus are involved in the acquisition, but not in the expression of morphine-induced place preference.

    PubMed

    Zarrindast, Mohammad-Reza; Lashgari, Reza; Rezayof, Ameneh; Motamedi, Fereshteh; Nazari-Serenjeh, Farzaneh

    2007-07-30

    In the present study, involvement of the N-methyl-d-aspartate (NMDA) receptors of the CA1 region of dorsal hippocampus (intra-CA1) in the acquisition or expression of morphine-induced conditioned place preference in rats was studied. Male Wistar rats were used in these experiments. NMDA-receptor agonist (NMDA) and antagonist (MK-801) were injected into the CA1 region of the dorsal hippocampus (intra-CA1) and morphine was injected subcutaneously. An unbiased conditioned place preference paradigm was used to study the effect of these agents. In the first set of experiments, the drugs were used during the development of conditioned place preference by morphine or they were used alone in order to see if they induce conditioned place preference or conditioned place aversion. Our data showed that subcutaneous (s.c.) injection of morphine sulphate (2.5-10 mg/kg) induced conditioned place preference in rat. NMDA (0.1-1 microg/rat) or MK-801 (1-4 microg/rat) did not induce conditioned place preference or conditioned place aversion. Intra-CA1 administration of different doses of NMDA (0.1-1 microg/rat) increased, while MK-801 (1-4 microg/rat) decreased morphine-induced place preference. MK-801 reversed the effect of NMDA on morphine response. In the second set of experiments, when the drugs were used before testing on Day 5, in order to test their effects on the expression of morphine (7.5 mg/kg)-induced place preference, intra-CA1 administration of NMDA or MK-801 did not alter the morphine response. None of the drugs influenced locomotion. It is concluded that NMDA receptor of the CA1 region of hippocampus are involved in the acquisition but not expression of morphine-induced place preference.

  9. Activation of matrix metalloproteinase in dorsal hippocampus drives improvement in spatial working memory after intra-VTA nicotine infusion in rats.

    PubMed

    Shu, Hui; Zheng, Guo-qing; Wang, Xiaona; Sun, Yanyun; Liu, Yushan; Weaver, John Michael; Shen, Xianzhi; Liu, Wenlan; Jin, Xinchun

    2015-10-01

    The hippocampus receives dopaminergic projections from the ventral tegmental area (VTA) and substantia nigra. These inputs appear to provide a modulatory signal that influences hippocampus-dependent behaviors. Enhancements in working memory performance have been previously reported following acute smoking/nicotine exposure. However, the underlying mechanism remains unclear. This study investigated the effects of nicotine on spatial working memory (SWM) and the mechanisms involved. Delayed alternation T-maze task was used to assess SWM. In situ and gel gelatin zymography were used to detect matrix metalloproteinase-9 (MMP-9) in SWM. Systemic or local (intra-VTA) administration of nicotine significantly improves SWM, which was accompanied by increased MMP-9 activity in dorsal hippocampus (dHPC). Intra-dHPC administration of MMP inhibitor FN-439 abolished the memory enhancement induced by intra-VTA nicotine infusion. FN-439 had no effect on locomotor behavior. Our data suggest that intra-VTA nicotine infusion activates MMP-9 in dHPC to improve SWM in rats.

  10. Sleep deprivation induces spatial memory impairment by altered hippocampus neuroinflammatory responses and glial cells activation in rats.

    PubMed

    Wadhwa, Meetu; Kumari, Punita; Chauhan, Garima; Roy, Koustav; Alam, Shahnawaz; Kishore, Krishna; Ray, Koushik; Panjwani, Usha

    2017-11-15

    We aimed to investigate the glial cells activation as a potential mechanism involved in the sleep deprivation (SD) induced cognitive impairment through changes in inflammatory cytokines. We analyzed the spatial memory, inflammatory cytokine levels, and gliosis during SD. SD induced spatial memory impairment, imbalance of inflammatory (increased pro- and decreased anti-) cytokines in both hippocampus and plasma in association with glial cells activation in the hippocampus of sleep-deprived rats were observed. Further analysis of the data presented a correlation between spatial memory impairment and activated microglia induced increased pro-inflammatory cytokines after 48h of SD. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Inhibition of Rac1 activity in the hippocampus impaired extinction of contextual fear.

    PubMed

    Jiang, Lizhu; Mao, Rongrong; Tong, Jianbin; Li, Jinnan; Chai, Anping; Zhou, Qixin; Yang, Yuexiong; Wang, Liping; Li, Lingjiang; Xu, Lin

    2016-10-01

    Promoting extinction of fear memory is the main treatment of fear disorders, especially post-traumatic stress disorder (PTSD). However, fear extinction is often incomplete in these patients. Our previous study had shown that Rac1 activity in hippocampus plays a crucial role in the learning of contextual fear memory in rats. Here, we further investigated whether Rac1 activity also modulated the extinction of contextual fear memory. We found that massed extinction obviously upregulated hippocampal Rac1 activity and induced long-term extinction of contextual fear in rats. Intrahippocampal injection of the Rac1 inhibitor NSC23766 prevents extinction of contextual fear in massed extinction training rats. In contrast, long-spaced extinction downregulated Rac1 activity and caused less extinction. And Rac1 activator CN04-A promotes extinction of contextual fear in long-spaced extinction rats. Our study demonstrates that inhibition of Rac1 activity in the hippocampus impaired extinction of contextual fear, suggesting that modulating Rac1 activity of the hippocampus may be promising therapy of fear disorders. Copyright © 2016 Elsevier Ltd. All rights reserved.

  12. Modulation of axonal sprouting along rostro-caudal axis of dorsal hippocampus and no neuronal survival in parahippocampal cortices by long-term post-lesion melatonin administration in lithium-pilocarpine model of temporal lobe epilepsy

    PubMed Central

    Ganjkhani, Mahin; Ali, Rostami; Iraj, Jafari Anarkooli

    2016-01-01

    Feature outcome of hippocampus and extra-hippocampal cortices was evaluated in melatonin treated lithium-pilocarpine epileptic rats during early and chronic phases of temporal lobe epilepsy (TLE). After status epilepticus (SE) induction, 5 and 20 mg/kg melatonin were administered for 14 days or 60 days. All animals were killed 60 days post SE induction and the histological features of the rosrto-caudal axis of the dorsal hippocampus, piriform and entorhinal cortices were evaluated utilizing Nissl, Timm, and synapsin I immunoflorescent staining. Melatonin (20 mg/kg) effect on CA1 and CA3 neurons showed a region-specific pattern along the rostro-caudal axis of the dorsal hippocampus. The number of counted granular cells by melatonin (20 mg/kg) treatment increased along the rostro-caudal axis of the dorsal hippocampus in comparison to the untreated epileptic group. The density of Timm granules in the inner molecular layer of the dentate gyrus decreased significantly in all melatonin treated groups in comparison to the untreated epileptic animals. The increased density of synapsin I immunoreactivity in the outer molecular layer of the dentate gyrus of untreated epileptic rats showed a profound decrease following melatonin treatment. There was no neuronal protection in the piriform and entorhinal cortices whatever the melatonin treatment. Long-term melatonin administration as a co-adjuvant probably could reduce the post-lesion histological consequences of TLE in a region-specific pattern along the rostro-caudal axis of the dorsal hippocampus. PMID:27051565

  13. Neurotoxic saboteurs: straws that break the hippo's (hippocampus) back drive cognitive impairment and Alzheimer's Disease.

    PubMed

    Daulatzai, Mak Adam

    2013-10-01

    Late onset Alzheimer's disease (AD) is the most common cause of progressive cognitive dysfunction and dementia. Despite considerable progress in elucidating the molecular pathology of this disease, we are not yet close to unraveling its etiopathogenesis. The hippocampus is at the epicenter of cognition being associated with learning and memory. A battery of neurotoxic modifiers has been delineated that may unleash deleterious heterogeneous pathologic impacts. Synergistically they target hippocampus causing its neuronal degeneration, gray matter volume atrophy, and progressive cognitive decline. The neurotoxic factors include aging, stress, depression, hypoxia/hypoxemia, hypertension, diabetes, obesity, alcohol abuse, smoking, malnutrition, and polypharmacy-to name a few. Addressing "upstream pathologies" due to these multiple and heterogeneous neurotoxic modifiers vis-a-vis hippocampal dysfunction is of paramount importance. The downstream-generated inflammatory cytokines, mitochondrial dysfunction, oxidative stress, hypoperfusion, excitotoxicity, amyloid beta, and neurofibrillary tangles may then trigger and sustain neurocognitive pathology. The failure of clinical trials in AD is due in part to this complex multifactorial neurotoxic-pathophysiological labyrinth. The key is to employ appropriate preventive and treatment strategies prior to significant hippocampus damage and its dysfunction. Prevention/reversal of the diverse neurotoxic impacts, delineated here, should be an integral part of therapeutic armamentarium, in order to ameliorate hippocampus dysfunction and to enhance memory in aging, mild cognitive impairment, and AD. Throughout, the paper highlights both the challenges presented by the ever present neurotoxic onslaught, and the opportunities to overcome them. Hence, arresting AD pathogenesis is achievable through early intervention. A targeted approach may ameliorate neurocognitive pathology and attenuate memory deterioration.

  14. Impaired Communication Between the Dorsal and Ventral Stream: Indications from Apraxia

    PubMed Central

    Evans, Carys; Edwards, Martin G.; Taylor, Lawrence J.; Ietswaart, Magdalena

    2016-01-01

    Patients with apraxia perform poorly when demonstrating how an object is used, particularly when pantomiming the action. However, these patients are able to accurately identify, and to pick up and move objects, demonstrating intact ventral and dorsal stream visuomotor processing. Appropriate object manipulation for skilled use is thought to rely on integration of known and visible object properties associated with “ventro-dorsal” stream neural processes. In apraxia, it has been suggested that stored object knowledge from the ventral stream may be less readily available to incorporate into the action plan, leading to an over-reliance on the objects’ visual affordances in object-directed motor behavior. The current study examined grasping performance in left hemisphere stroke patients with (N = 3) and without (N = 9) apraxia, and in age-matched healthy control participants (N = 14), where participants repeatedly grasped novel cylindrical objects of varying weight distribution. Across two conditions, object weight distribution was indicated by either a memory-associated cue (object color) or visual-spatial cue (visible dot over the weighted end). Participants were required to incorporate object-weight associations to effectively grasp and balance each object. Control groups appropriately adjusted their grasp according to each object’s weight distribution across each condition, whereas throughout the task two of the three apraxic patients performed poorly on both the memory-associated and visual-spatial cue conditions. A third apraxic patient seemed to compensate for these difficulties but still performed differently to control groups. Patients with apraxia performed normally on the neutral control condition when grasping the evenly weighted version. The pattern of behavior in apraxic patients suggests impaired integration of visible and known object properties attributed to the ventro-dorsal stream: in learning to grasp the weighted object accurately, apraxic

  15. Activation of dopaminergic D2/D3 receptors modulates dorsoventral connectivity in the hippocampus and reverses the impairment of working memory after nerve injury.

    PubMed

    Cardoso-Cruz, Helder; Dourado, Margarida; Monteiro, Clara; Matos, Mariana R; Galhardo, Vasco

    2014-04-23

    Dopamine plays an important role in several forms of synaptic plasticity in the hippocampus, a crucial brain structure for working memory (WM) functioning. In this study, we evaluated whether the working-memory impairment characteristic of animal models of chronic pain is dependent on hippocampal dopaminergic signaling. To address this issue, we implanted multichannel arrays of electrodes in the dorsal and ventral hippocampal CA1 region of rats and recorded the neuronal activity during a food-reinforced spatial WM task of trajectory alternation. Within-subject behavioral performance and patterns of dorsoventral neuronal activity were assessed before and after the onset of persistent neuropathic pain using the Spared Nerve Injury (SNI) model of neuropathic pain. Our results show that the peripheral nerve lesion caused a disruption in WM and in hippocampus spike activity and that this disruption was reversed by the systemic administration of the dopamine D2/D3 receptor agonist quinpirole (0.05 mg/kg). In SNI animals, the administration of quinpirole restored both the performance-related and the task-related spike activity to the normal range characteristic of naive animals, whereas quinpirole in sham animals caused the opposite effect. Quinpirole also reversed the abnormally low levels of hippocampus dorsoventral connectivity and phase coherence. Together with our finding of changes in gene expression of dopamine receptors and modulators after the onset of the nerve injury model, these results suggest that disruption of the dopaminergic balance in the hippocampus may be crucial for the clinical neurological and cognitive deficits observed in patients with painful syndromes.

  16. Formaldehyde impairs learning and memory involving the disturbance of hydrogen sulfide generation in the hippocampus of rats.

    PubMed

    Tang, Xiao-Qing; Zhuang, Yuan-Yuan; Zhang, Ping; Fang, Heng-Rong; Zhou, Cheng-Fang; Gu, Hong-Feng; Zhang, Hui; Wang, Chun-Yan

    2013-01-01

    Formaldehyde (FA), a well-known indoor and outdoor pollutant, has been implicated as the responsible agent in the development of neurocognitive disorders. Hydrogen sulfide (H(2)S), the third gasotransimitter, is an endogenous neuromodulator, which facilitates the induction of hippocampal long-term potentiation, involving the functions of learning and memory. In the present study, we analyzed the effects of intracerebroventricular injection of FA on the formation of learning and memory and the generation of endogenous H(2)S in the hippocampus of rats. We found that the intracerebroventricular injection of FA in rats impairs the function of learning and memory in the Morris water maze and novel object recognition test and increases the formation of apoptosis and lipid peroxidation in the hippocampus. We also showed that FA exposure inhibits the expression of cystathionine β-synthase, the major enzyme responsible for endogenous H(2)S generation in hippocampus and decreases the production of endogenous H(2)S in hippocampus in rats. These results suggested that FA-disturbed generation of endogenous H(2)S in hippocampus leads to the oxidative stress-mediated neuron damage, ultimately impairing the function of learning and memory. Our findings imply that the disturbance of endogenous H(2)S generation in hippocampus is a potential contributing mechanism underling FA-caused learning and memory impairment.

  17. Antidepressant suppression of non-REM sleep spindles and REM sleep impairs hippocampus-dependent learning while augmenting striatum-dependent learning.

    PubMed

    Watts, Alain; Gritton, Howard J; Sweigart, Jamie; Poe, Gina R

    2012-09-26

    Rapid eye movement (REM) sleep enhances hippocampus-dependent associative memory, but REM deprivation has little impact on striatum-dependent procedural learning. Antidepressant medications are known to inhibit REM sleep, but it is not well understood if antidepressant treatments impact learning and memory. We explored antidepressant REM suppression effects on learning by training animals daily on a spatial task under familiar and novel conditions, followed by training on a procedural memory task. Daily treatment with the antidepressant and norepinephrine reuptake inhibitor desipramine (DMI) strongly suppressed REM sleep in rats for several hours, as has been described in humans. We also found that DMI treatment reduced the spindle-rich transition-to-REM sleep state (TR), which has not been previously reported. DMI REM suppression gradually weakened performance on a once familiar hippocampus-dependent maze (reconsolidation error). DMI also impaired learning of the novel maze (consolidation error). Unexpectedly, learning of novel reward positions and memory of familiar positions were equally and oppositely correlated with amounts of TR sleep. Conversely, DMI treatment enhanced performance on a separate striatum-dependent, procedural T-maze task that was positively correlated with the amounts of slow-wave sleep (SWS). Our results suggest that learning strategy switches in patients taking REM sleep-suppressing antidepressants might serve to offset sleep-dependent hippocampal impairments to partially preserve performance. State-performance correlations support a model wherein reconsolidation of hippocampus-dependent familiar memories occurs during REM sleep, novel information is incorporated and consolidated during TR, and dorsal striatum-dependent procedural learning is augmented during SWS.

  18. Enhanced limbic/impaired cortical-loop connection onto the hippocampus of NHE rats: Application of resting-state functional connectivity in a preclinical ADHD model.

    PubMed

    Zoratto, F; Palombelli, G M; Ruocco, L A; Carboni, E; Laviola, G; Sadile, A G; Adriani, W; Canese, R

    2017-08-30

    Due to a hyperfunctioning mesocorticolimbic system, Naples-High-Excitability (NHE) rats have been proposed to model for the meso-cortical variant of attention deficit/hyperactivity disorder (ADHD). Compared to Naples Random-Bred (NRB) controls, NHE rats show hyperactivity, impaired non-selective attention (Aspide et al., 1998), and impaired selective spatial attention (Ruocco et al., 2009a, 2014). Alteration in limbic functions has been proposed; however, resulting unbalance among forebrain areas has not been assessed yet. By resting-state functional Magnetic-Resonance Imaging (fMRI) in vivo, we investigated the connectivity of neuronal networks belonging to limbic vs. cortical loops in NHE and NRB rats (n=10 each). Notably, resting-state fMRI was applied using a multi-slice sagittal, gradient-echo sequence. Voxel-wise connectivity maps at rest, based on temporal correlation among fMRI time-series, were computed by seeding the hippocampus (Hip), nucleus accumbens (NAcc), dorsal striatum (dStr), amygdala (Amy) and dorsal/medial prefrontal cortex (PFC), both hemispheres. To summarize patterns of altered connection, clearly directional connectivity was evident within the cortical loop: bilaterally and specularly, from orbital and dorsal PFCs through dStr and hence towards Hip. Such network communication was reduced in NHE rats (also, with less mesencephalic/pontine innervation). Conversely, enhanced network activity emerged within the limbic loop of NHE rats: from left PFC, both through the NAcc and directly, to the Hip (all of which received greater ventral tegmental innervation, likely dopamine). Together with tuned-down cortical loop, this potentiated limbic loop may serve a major role in controlling ADHD-like behavioral symptoms in NHE rats. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Estradiol-Induced Object Recognition Memory Consolidation Is Dependent on Activation of mTOR Signaling in the Dorsal Hippocampus

    ERIC Educational Resources Information Center

    Fortress, Ashley M.; Fan, Lu; Orr, Patrick T.; Zhao, Zaorui; Frick, Karyn M.

    2013-01-01

    The mammalian target of rapamycin (mTOR) signaling pathway is an important regulator of protein synthesis and is essential for various forms of hippocampal memory. Here, we asked whether the enhancement of object recognition memory consolidation produced by dorsal hippocampal infusion of 17[Beta]-estradiol (E[subscript 2]) is dependent on mTOR…

  20. Estradiol-Induced Object Recognition Memory Consolidation Is Dependent on Activation of mTOR Signaling in the Dorsal Hippocampus

    ERIC Educational Resources Information Center

    Fortress, Ashley M.; Fan, Lu; Orr, Patrick T.; Zhao, Zaorui; Frick, Karyn M.

    2013-01-01

    The mammalian target of rapamycin (mTOR) signaling pathway is an important regulator of protein synthesis and is essential for various forms of hippocampal memory. Here, we asked whether the enhancement of object recognition memory consolidation produced by dorsal hippocampal infusion of 17[Beta]-estradiol (E[subscript 2]) is dependent on mTOR…

  1. Chronic developmental lead exposure reduces neurogenesis in adult rat hippocampus but does not impair spatial learning.

    PubMed

    Gilbert, M E; Kelly, M E; Samsam, T E; Goodman, J H

    2005-08-01

    The dentate granule cell (DG) layer of the hippocampal formation has the distinctive property of ongoing neurogenesis that continues throughout adult life. Although the function of these newly generated neurons and the mechanisms that control their birth are unknown, age, activity, diet and psychosocial stress have all been demonstrated to regulate this type of neurogenesis. Little information on the impact of environmental insults on this process has appeared to date. Developmental lead (Pb) exposure has been well documented to impair cognitive function in children and animals and reduce activity-dependent synaptic plasticity in the hippocampus of rodents. Therefore, we examined the effects of this classic environmental neurotoxicant on hippocampal-dependent learning and adult neurogenesis in the hippocampus. Pregnant rats were exposed to a low level of Pb-acetate (0.2%) via the drinking water from late gestation (GD 16) until weaning on postnatal day 21 (PN 21). At weaning, half of the Pb-exposed animals were weaned to control drinking water and the remainder were maintained on Pb water until termination of the study. Animals were paired- housed and on PN 75 were administered a series of injections of a thymidine analog bromodeoxyuridine (BrdU), a marker of DNA synthesis that labels proliferating cells and their progeny. At 12-h intervals for 12 days, rats received an ip injection of BrdU (50 mg/kg). Subjects were sacrificed and perfused 24 h and 28 days after the last injection. Spatial learning was assessed in an independent group of animals beginning on PN 110 using a Morris water maze. No Pb-induced impairments were evident in water maze learning. Immunohistochemistry for the detection of BrdU-labeled cells was performed on 40-microm coronal sections throughout the hippocampus. Continuous exposure to Pb (Life) reduced the total number of BrdU-positive cells at 28 days without affecting the total number of labeled cells evident 24 h after the last injection

  2. Dietary omega-3 deficiency reduces BDNF content and activation NMDA receptor and Fyn in dorsal hippocampus: implications on persistence of long-term memory in rats.

    PubMed

    Bach, Simone Azevedo; de Siqueira, Letícia V; Müller, Alexandre P; Oses, Jean P; Quatrim, Andreia; Emanuelli, Tatiana; Vinadé, Lúcia; Souza, Diogo O; Moreira, Júlia D

    2014-07-01

    Omega-3 (n-3) fatty acids are important for adequate brain function and cognition. The aim of the present study was to evaluate how n-3 fatty acids influence the persistence of long-term memory (LTM) in an aversive memory task and to explore the putative mechanism involved. Female rats received isocaloric diets that included n-3 (n-3 group) or not (D group). The adult litters were subjected to an inhibitory avoidance task (0.7 mA, 1.0 seconds foot shock) to elicit persistent LTM. Twelve hours after the training session, the fatty acid profile and the brain derived neurotrophic factor (BDNF) content of the dorsal hippocampus were assessed. In addition, we measured the activation of the NR2B subunit of the N-methyl-d-aspartate (NMDA) receptor and the SRC family protein Fyn. Despite pronounced learning in both groups, the persistence of LTM was abolished in the D group 7 days after the training session. We also observed that the D group presented reductions in hippocampal DHA (22:6 n-3) and BDNF content. Twelve hours after the training session, the D group showed decreased NR2B and Fyn phosphorylation in the dorsal hippocampus, with no change in the total content of these proteins. Further, there was a decrease in the interaction of Fyn with NR2B in the D group, as observed by co-immunoprecipitation. Taken together, these data suggest that n-3 fatty acids influence the persistence of LTM by maintaining adequate levels of DHA and BDNF as well as by influencing the activation of NR2B and Fyn during the period of memory formation.

  3. Preictal Activity of Subicular, CA1, and Dentate Gyrus Principal Neurons in the Dorsal Hippocampus before Spontaneous Seizures in a Rat Model of Temporal Lobe Epilepsy

    PubMed Central

    Fujita, Satoshi; Toyoda, Izumi; Thamattoor, Ajoy K.

    2014-01-01

    Previous studies suggest that spontaneous seizures in patients with temporal lobe epilepsy might be preceded by increased action potential firing of hippocampal neurons. Preictal activity is potentially important because it might provide new opportunities for predicting when a seizure is about to occur and insight into how spontaneous seizures are generated. We evaluated local field potentials and unit activity of single, putative excitatory neurons in the subiculum, CA1, CA3, and dentate gyrus of the dorsal hippocampus in epileptic pilocarpine-treated rats as they experienced spontaneous seizures. Average action potential firing rates of neurons in the subiculum, CA1, and dentate gyrus, but not CA3, increased significantly and progressively beginning 2–4 min before locally recorded spontaneous seizures. In the subiculum, CA1, and dentate gyrus, but not CA3, 41–57% of neurons displayed increased preictal activity with significant consistency across multiple seizures. Much of the increased preictal firing of neurons in the subiculum and CA1 correlated with preictal theta activity, whereas preictal firing of neurons in the dentate gyrus was independent of theta. In addition, some CA1 and dentate gyrus neurons displayed reduced firing rates preictally. These results reveal that different hippocampal subregions exhibit differences in the extent and potential underlying mechanisms of preictal activity. The finding of robust and significantly consistent preictal activity of subicular, CA1, and dentate neurons in the dorsal hippocampus, despite the likelihood that many seizures initiated in other brain regions, suggests the existence of a broader neuronal network whose activity changes minutes before spontaneous seizures initiate. PMID:25505320

  4. A Potential VEP Biomarker for Mild Cognitive Impairment: Evidence from Selective Visual Deficit of Higher-Level Dorsal Pathway.

    PubMed

    Yamasaki, Takao; Horie, Shizuka; Ohyagi, Yasumasa; Tanaka, Eri; Nakamura, Norimichi; Goto, Yoshinobu; Kanba, Shigenobu; Kira, Jun-Ichi; Tobimatsu, Shozo

    2016-05-23

    Visual dysfunctions are common in Alzheimer's disease (AD). Our aim was to establish a neurophysiological biomarker for amnestic mild cognitive impairment (aMCI). Visual evoked potentials (VEPs) were recorded in aMCI patients who later developed AD (n = 15) and in healthy older (n = 15) and younger controls (n = 15). Visual stimuli were optimized to separately activate lower and higher levels of the ventral and dorsal streams. We compared VEP parameters across the three groups of participants and conducted a linear correlation analysis between VEPs and data from neuropsychological tests. We then used a receiver operating characteristic (ROC) analysis to discriminate those with aMCI from those who were healthy older adults. The latency and phase of VEPs to lower-level stimuli (chromatic and achromatic gratings) were significantly affected by age but not by cognitive decline. Conversely, VEP latencies for higher-ventral (faces and kanji-words) and dorsal (kana-words and optic flow motion) stimuli were not affected by age, but they were significantly prolonged in aMCI patients. Interestingly, VEPs for higher-dorsal stimuli were related to outcomes of neuropsychological tests. Furthermore, the ROC analysis showed that the highest areas under the curve were obtained for VEP latencies in response to higher-dorsal stimuli. These results suggest aMCI-related functional impairment specific to higher-level visual processing. Further, dysfunction in the higher-level of the dorsal stream could be an early indicator of cognitive decline. Therefore, we conclude that VEPs associated with higher-level dorsal stream activity can be a sensitive biomarker for early detection of aMCI.

  5. Adult-onset focal expression of mutated human tau in the hippocampus impairs spatial working memory of rats.

    PubMed

    Mustroph, Martina L; King, Michael A; Klein, Ronald L; Ramirez, Julio J

    2012-07-15

    Tauopathy in the hippocampus is one of the earliest cardinal features of Alzheimer's disease (AD), a condition characterized by progressive memory impairments. In fact, density of tau neurofibrillary tangles (NFTs) in the hippocampus strongly correlates with severity of cognitive impairments in AD. In the present study, we employed a somatic cell gene transfer technique to create a rodent model of tauopathy by injecting a recombinant adeno-associated viral vector with a mutated human tau gene (P301L) into the hippocampus of adult rats. The P301L mutation is causal for frontotemporal dementia with parkinsonism-17 (FTDP-17), but it has been used for studying memory effects characteristic of AD in transgenic mice. To ascertain if P301L-induced mnemonic deficits are persistent, animals were tested for 6 months. It was hypothesized that adult-onset, spatially restricted tau expression in the hippocampus would produce progressive spatial working memory deficits on a learned alternation task. Rats injected with the tau vector exhibited persistent impairments on the hippocampal-dependent task beginning at about 6 weeks post-transduction compared to rats injected with a green fluorescent protein vector. Histological analysis of brains for expression of human tau revealed hyperphosphorylated human tau and NFTs in the hippocampus in experimental animals only. Thus, adult-onset, vector-induced tauopathy spatially restricted to the hippocampus progressively impaired spatial working memory in rats. We conclude that the model faithfully reproduces histological and behavioral findings characteristic of dementing tauopathies. The rapid onset of sustained memory impairment establishes a preclinical model particularly suited to the development of potential tauopathy therapeutics.

  6. Extremely low-frequency electromagnetic field exposure during chronic morphine treatment strengthens downregulation of dopamine D2 receptors in rat dorsal hippocampus after morphine withdrawal.

    PubMed

    Wang, Xiusong; Liu, Yadong; Lei, Yanlin; Zhou, Dongming; Fu, Yu; Che, Yi; Xu, Ruchang; Yu, Hualin; Hu, Xintian; Ma, Yuanye

    2008-03-15

    The aim of this study was to investigate the effect of extremely low-frequency electromagnetic field (ELF-EMF) exposure during morphine treatment on dopamine D2 receptor (D2R) density in the rat dorsal hippocampus following withdrawal. Rats were exposed to ELF-EMF (20 Hz, 14 mT) or sham exposed for 1h per day before injection of morphine (10mg/kg, i.p.) once daily for 12 days. The saline control group was sham exposed for the same period. Immunohistochemistry was used to detect the density of D2Rs on the 1st, 3rd and 5th morphine withdrawal days. The results showed that the density of D2Rs in sham-exposed morphine-treated rats on the 1st and 3rd days of morphine withdrawal was significantly lower than that of the saline control group. The ELF-EMF-exposed morphine group also exhibited a significantly lower density of D2Rs on the 1st and 3rd withdrawal days relative to the sham-exposed morphine group. However, the D2R density in both groups tended to recover as morphine withdrawal days increased. The results suggest that dorsal hippocampal D2Rs are sensitive to morphine withdrawal and that this is potentiated by ELF-EMF pre-exposure during morphine treatment.

  7. Neurokinin-1 (NK-1) receptor and brain-derived neurotrophic factor (BDNF) gene expression is differentially modulated in the rat spinal dorsal horn and hippocampus during inflammatory pain.

    PubMed

    Duric, Vanja; McCarson, Kenneth E

    2007-10-31

    Persistent pain produces complex alterations in sensory pathways of the central nervous system (CNS) through activation of various nociceptive mechanisms. However, the effects of pain on higher brain centers, particularly the influence of the stressful component of pain on the limbic system, are poorly understood. Neurokinin-1 (NK-1) receptors and brain-derived neurotrophic factor (BDNF), known neuromediators of hyperalgesia and spinal central sensitization, have also been implicated in the plasticity and neurodegeneration occurring in the hippocampal formation during exposures to various stressors. Results of this study showed that injections of complete Freund's adjuvant (CFA) into the hind paw increased NK-1 receptor and BDNF mRNA levels in the ipsilateral dorsal horn, supporting an important role for these nociceptive mediators in the amplification of ascending pain signaling. An opposite effect was observed in the hippocampus, where CFA down-regulated NK-1 receptor and BDNF gene expression, phenomena previously observed in immobilization models of stress and depression. Western blot analyses demonstrated that in the spinal cord, CFA also increased levels of phosphorylated cAMP response element-binding protein (CREB), while in the hippocampus the activation of this transcription factor was significantly reduced, further suggesting that tissue specific transcription of either NK-1 or BDNF genes may be partially regulated by common intracellular transduction mechanisms mediated through activation of CREB. These findings suggest that persistent nociception induces differential regional regulation of NK-1 receptor and BDNF gene expression and CREB activation in the CNS, potentially reflecting varied roles of these neuromodulators in the spinal cord during persistent sensory activation vs. modulation of the higher brain structures such as the hippocampus.

  8. CREB Antisense Oligodeoxynucleotide Administration into the Dorsal Hippocampal CA3 Region Impairs Long- but Not Short-Term Spatial Memory in Mice

    ERIC Educational Resources Information Center

    Florian, Cedrick; Mons, Nicole; Roullet, Pascal

    2006-01-01

    The transcription factor cAMP response-element binding protein (CREB) has a pivotal role in hippocampal synaptic plasticity and hippocampus-dependent long-term memory. We recently demonstrated that the dorsal hippocampal CA3 region is involved in memory consolidation of spatial information tested on a Morris water maze in mice. To test whether…

  9. Less depressive symptoms are associated with smaller hippocampus in subjective memory impairment.

    PubMed

    Kim, Min-Jeong; Seo, Sang Won; Kim, Geon Ha; Kim, Sung Tae; Lee, Jong-Min; Qiu, Anqi; Na, Duk L

    2013-01-01

    Although individuals with subjective memory impairment (SMI) tend to be at an increased risk for dementia and the majority of them have depressive symptoms, it remains unclear whether SMI with depression is associated with an increased or decreased risk of dementia. The purpose of this study was to investigate the relationship between depressive symptoms and hippocampal/amygdalar volume, a reliable biomarker in the prediction of progression to dementia in SMI. Ninety subjects with SMI participated in the study, and 28 healthy participants without memory complaints served as a normal control (NC) group. 3-D T1-weighted structural MRI scans were completed in all subjects. When the volumes of hippocampus and amygdala were compared among the groups, the SMI group showed significantly smaller volumes than the NC group. When multiple regression analysis was conducted in all subjects, neither hippocampal nor amygdalar volume showed significant interaction effect between group and Geriatric Depression Scale (GDS). However, when the analysis was conducted within each group, lower GDS score was associated with smaller hippocampal volume in the SMI group, and higher GDS score was associated with smaller amygdalar volume in the NC group. Thus, individuals with SMI and less depressive symptoms tend to have smaller hippocampus, which could be associated with more risk of dementia, than normal individuals.

  10. Long-term intermittent feeding restores impaired GR signaling in the hippocampus of aged rat.

    PubMed

    Tesic, Vesna; Perovic, Milka; Lazic, Divna; Kojic, Snezana; Smiljanic, Kosara; Ruzdijic, Sabera; Rakic, Ljubisav; Kanazir, Selma

    2015-05-01

    Diminished glucocorticoid signaling is associated with an age-related decline in hippocampal functioning. In this study we demonstrate the effect of intermittent, every other day (EOD) feeding on the glucocorticoid hormone/glucocorticoid receptor (GR) system in the hippocampus of middle-aged (18-month-old) and aged (24-month-old) Wistar rats. In aged ad libitum-fed rats, a decrease in the level of total GR and GR phosphorylated at Ser(232) (pGR) was detected. Conversely, aged rats subjected to EOD feeding, starting from 6 months of age, showed an increase in GR and pGR levels and a higher content of hippocampal corticosterone. Furthermore, prominent nuclear staining of pGR was observed in CA1 pyramidal and DG granule neurons of aged EOD-fed rats. These changes were accompanied by increased Sgk-1 and decreased GFAP transcription, pointing to upregulated transcriptional activity of GR. EOD feeding also induced an increase in the expression of the mineralocorticoid receptor. Our results reveal that intermittent feeding restores impaired GR signaling in the hippocampus of aged animals by inducing rather than by stabilizing GR signaling during aging.

  11. Methylphenidate Causes Behavioral Impairments and Neuron and Astrocyte Loss in the Hippocampus of Juvenile Rats.

    PubMed

    Schmitz, Felipe; Pierozan, Paula; Rodrigues, André F; Biasibetti, Helena; Grunevald, Matheus; Pettenuzzo, Letícia F; Scaini, Giselli; Streck, Emilio L; Netto, Carlos A; Wyse, Angela T S

    2017-08-01

    Although the use, and misuse, of methylphenidate is increasing in childhood and adolescence, there is little information about the consequences of this psychostimulant chronic use on brain and behavior during development. The aim of the present study was to investigate hippocampus biochemical, histochemical, and behavioral effects of chronic methylphenidate treatment to juvenile rats. Wistar rats received intraperitoneal injections of methylphenidate (2.0 mg/kg) or an equivalent volume of 0.9 % saline solution (controls), once a day, from the 15th to the 45th day of age. Results showed that chronic methylphenidate administration caused loss of astrocytes and neurons in the hippocampus of juvenile rats. BDNF and pTrkB immunocontents and NGF levels were decreased, while TNF-α and IL-6 levels, Iba-1 and caspase 3 cleaved immunocontents (microglia marker and active apoptosis marker, respectively) were increased. ERK and PKCaMII signaling pathways, but not Akt and GSK-3β, were decreased. SNAP-25 was decreased after methylphenidate treatment, while GAP-43 and synaptophysin were not altered. Both exploratory activity and object recognition memory were impaired by methylphenidate. These findings provide additional evidence that early-life exposure to methylphenidate can have complex effects, as well as provide new basis for understanding of the biochemical and behavioral consequences associated with chronic use of methylphenidate during central nervous system development.

  12. Depletion of primary cilia from mature dentate granule cells impairs hippocampus-dependent contextual memory

    PubMed Central

    Rhee, Soyoung; Kirschen, Gregory W.; Gu, Yan; Ge, Shaoyu

    2016-01-01

    The primary cilium, a sensory organelle, regulates cell proliferation and neuronal development of dentate granule cells in the hippocampus. However, its role in the function of mature dentate granule cells remains unknown. Here we specifically depleted and disrupted ciliary proteins IFT20 and Kif3A (respectively) in mature dentate granule cells and investigated hippocampus-dependent contextual memory and long-term plasticity at mossy fiber synapses. We found that depletion of IFT20 in these cells significantly impaired context-dependent fear-related memory. Furthermore, we tested synaptic plasticity of mossy fiber synapses in area CA3 and found increased long-term potentiation upon depletion of IFT20 or disruption of Kif3A. Our findings suggest a role of primary cilia in the memory function of mature dentate granule cells, which may result from abnormal mossy fiber synaptic plasticity. A direct link between the primary cilia of mature dentate granule cells and behavior will require further investigation using independent approaches to manipulate primary cilia. PMID:27678193

  13. Chronic stress reduces the number of GABAergic interneurons in the adult rat hippocampus, dorsal-ventral and region-specific differences.

    PubMed

    Czéh, Boldizsár; Varga, Zsófia K Kalangyáné; Henningsen, Kim; Kovács, Gábor L; Miseta, Attila; Wiborg, Ove

    2015-03-01

    Major depressive disorder is a common and complex mental disorder with unknown etiology. GABAergic dysfunction is likely to contribute to the pathophysiology since disrupted GABAergic systems are well documented in depressed patients. Here we studied structural changes in the hippocampal GABAergic network using the chronic mild stress (CMS) model, as one of the best validated animal models for depression. Rats were subjected to 9 weeks of daily stress and behaviorally characterized using the sucrose consumption test into anhedonic and resilient animals based on their response to stress. Different subtypes of GABAergic interneurons were visualized by immunohistochemistry using antibodies for parvalbumin (PV), calretinin (CR), calbindin (CB), cholecystokinin (CCK), somatostatin (SOM), and neuropeptide Y (NPY). We used an unbiased quantification method to systematically count labeled cells in different subareas of the dorsal and ventral hippocampus. Chronic stress reduced the number of specific interneurons in distinct hippocampal subregions significantly. PV+ and CR+ neurons were reduced in all dorsal subareas, whereas in the ventral part only the CA1 was affected. Stress had the most pronounced effect on the NPY+ and SOM+ cells and reduced their number in almost all dorsal and ventral subareas. Stress had no effect on the CCK+ and CB+ interneurons. In most cases the effect of stress was irrespective to the behavioral phenotype. However, in a few specific areas the number of SOM+, NPY+, and CR+ neurons were significantly reduced in anhedonic animals compared to the resilient group. Overall, these data clearly demonstrate that chronic stress affects the structural integrity of specific GABAergic neuronal subpopulations and this should also affect the functioning of these hippocampal GABAergic networks.

  14. Microinfusion of the non-competitive N-methyl-D-aspartate receptor antagonist MK-801 (dizocilpine) into the dorsal hippocampus of wistar rats does not affect latent inhibition and prepulse inhibition, but increases startle reaction and locomotor activity.

    PubMed

    Zhang, W N; Bast, T; Feldon, J

    2000-01-01

    Latent inhibition (the retarded conditioning to a stimulus following its repeated non-reinforced pre-exposure) and prepulse inhibition (the reduction in the startle response to an intense acoustic stimulus when this stimulus is immediately preceded by a prepulse) reflect cognitive and sensorimotor gating processes, respectively, and are deficient in schizophrenic patients. The disruption of latent inhibition and prepulse inhibition in the rat is used as an animal model for the attentional deficits associated with schizophrenia. The present study tested the extent to which latent inhibition and prepulse inhibition, startle reaction and locomotor activity in the open field were affected by infusing the non-competitive N-methyl-D-aspartate receptor antagonist MK-801 (dizocilpine) into the dorsal hippocampus of Wistar rats. We used the same dose of MK-801 (6.25microg/0.5microl per side) previously found to be effective in the disruption of prepulse inhibition when infused into the dorsal hippocampus of Sprague-Dawley rats [Bakshi V. P. and Geyer M. A. (1998) J. Neurosci. 18, 8394-8401; Bakshi V. P. and Geyer M. A. (1999) Neuroscience 92, 113-121]. Bilateral infusion of MK-801 into the dorsal hippocampus did not disrupt latent inhibition. Furthermore, in contrast to previous studies, we failed to find a significant disruption of prepulse inhibition after MK-801 infusion into the dorsal hippocampus, although MK-801 infusion was effective in increasing the startle amplitude as well as locomotor activity in an open field. From our results, we suggest that N-methyl-D-aspartate receptor-mediated processes within the dorsal hippocampus are not necessary for the normal maintenance of the attentional processes reflected by latent inhibition and prepulse inhibition.

  15. Assessment of the Medial Dorsal Cutaneous, Dorsal Sural, and Medial Plantar Nerves in Impaired Glucose Tolerance and Diabetic Patients With Normal Sural and Superficial Peroneal Nerve Responses

    PubMed Central

    Im, Sun; Kim, Sung-Rae; Park, Joo Hyun; Kim, Yang Soo; Park, Geun-Young

    2012-01-01

    OBJECTIVE This study evaluated the nerve conduction study (NCS) parameters of the most distal sensory nerves of the lower extremities—namely, the medial dorsal cutaneous (MDC), dorsal sural (DS), and medial plantar (MP) nerves—in diabetic (DM) and impaired glucose tolerance (IGT) patients who displayed normal findings on their routine NCSs. RESEARCH DESIGN AND METHODS Standard NCSs were performed on healthy control (HC), DM, and IGT groups (N = 147). The bilateral NCS parameters of the MDC, DS, and MP nerves were investigated. The Toronto Clinical Scoring System (TCSS) was assessed for the DM and IGT groups. RESULTS The mean TCSS scores of the IGT and DM groups were 2.5 ± 2.3 and 2.8 ± 2.2, respectively. No significant differences between the two groups were observed. After adjustment of age and BMI, the DM group showed significant NCS differences in DS and MDC nerves compared with the HC group (P < 0.05). These differences were also exhibited in the left DS of the IGT group (P = 0.0003). More advanced NCS findings were observed in the DM group. Bilateral abnormal NCS responses in these distal sensory nerves were found in 40 and 16% of DM and IGT patients, respectively. CONCLUSIONS These results showed that the simultaneous assessment of the most distal sensory nerves allowed the detection of early NCS changes in the IGT and DM groups, even when the routine NCS showed normal findings. PMID:22100966

  16. Assessment of the medial dorsal cutaneous, dorsal sural, and medial plantar nerves in impaired glucose tolerance and diabetic patients with normal sural and superficial peroneal nerve responses.

    PubMed

    Im, Sun; Kim, Sung-Rae; Park, Joo Hyun; Kim, Yang Soo; Park, Geun-Young

    2012-04-01

    This study evaluated the nerve conduction study (NCS) parameters of the most distal sensory nerves of the lower extremities-namely, the medial dorsal cutaneous (MDC), dorsal sural (DS), and medial plantar (MP) nerves-in diabetic (DM) and impaired glucose tolerance (IGT) patients who displayed normal findings on their routine NCSs. Standard NCSs were performed on healthy control (HC), DM, and IGT groups (N = 147). The bilateral NCS parameters of the MDC, DS, and MP nerves were investigated. The Toronto Clinical Scoring System (TCSS) was assessed for the DM and IGT groups. The mean TCSS scores of the IGT and DM groups were 2.5 ± 2.3 and 2.8 ± 2.2, respectively. No significant differences between the two groups were observed. After adjustment of age and BMI, the DM group showed significant NCS differences in DS and MDC nerves compared with the HC group (P < 0.05). These differences were also exhibited in the left DS of the IGT group (P = 0.0003). More advanced NCS findings were observed in the DM group. Bilateral abnormal NCS responses in these distal sensory nerves were found in 40 and 16% of DM and IGT patients, respectively. These results showed that the simultaneous assessment of the most distal sensory nerves allowed the detection of early NCS changes in the IGT and DM groups, even when the routine NCS showed normal findings.

  17. Correlations between cognitive impairment and brain‑derived neurotrophic factor expression in the hippocampus of post-stroke depression rats.

    PubMed

    Zhang, Zhao-Hui; Wu, Li-Na; Song, Jing-Gui; Li, Wen-Qiang

    2012-10-01

    The aim of this study was to investigate the correlation between brain-derived neurotrophic factor (BDNF) expression and cognitive impairment in post‑stroke depression (PSD) rats and to explore the mechanism(s) involved in the process of cognitive impairment. A rat model of focal cerebral ischemia was established by occluding the middle cerebral artery (MCA). Rats were subjected to isolation-housing combined with chronic unexpected mild stress (CUMS) to establish a PSD rat model. The learning and memory abilities of the PSD rat model were evaluated by passive avoidance tests. Real‑time PCR and immunohistochemical methods were used to detect changes in BDNF mRNA and protein expression in the hippocampus. Passive avoidance defects were revealed in the PSD and depression groups. Passive avoidance defects were more evident in the PSD group compared with the depression group and the difference was statistically significant (P<0.05). BDNF expression in the hippocampus was significantly lower in the PSD and depression groups compared with that in the normal control group (P<0.01). No significant difference in BDNF expression was identified between the normal control and stroke groups (P>0.05) or between the PSD and the depression groups (P>0.05). The decrease in BDNF expression in the hippocampus of PSD rats may aggravate cognitive impairment, however, the degree of cognitive impairment cannot be reflected by the expression levels of BDNF in the hippocampus.

  18. Effects of dihydrotestosterone on synaptic plasticity of the hippocampus in mild cognitive impairment male SAMP8 mice

    PubMed Central

    Pan, Wensen; Han, Shuo; Kang, Lin; Li, Sha; Du, Juan; Cui, Huixian

    2016-01-01

    The current study focused on how dihydrotestosterone (DHT) regulates synaptic plasticity in the hippocampus of mild cognitive impairment male senescence-accelerated mouse prone 8 (SAMP8) mice. Five-month-old SAMP8 mice were divided into the control, castrated and castrated-DHT groups, in which the mice were castrated and treated with physiological doses of DHT for a period of 2 months. To determine the regulatory mechanisms of DHT in the cognitive capacity, the effects of DHT on the morphology of the synapse and the expression of synaptic marker proteins in the hippocampus were investigated using immunohistochemistry, qPCR and western blot analysis. The results showed that the expression of cAMP-response element binding protein (CREB), postsynaptic density protein 95 (PSD95), synaptophysin (SYN) and developmentally regulated brain protein (Drebrin) was reduced in the castrated group compared to the control group. However, DHT promoted the expression of CREB, PSD95, SYN and Drebrin in the hippocampus of the castrated-DHT group. Thus, androgen depletion impaired the synaptic plasticity in the hippocampus of SAMP8 and accelerated the development of Alzheimer's disease (AD)-like neuropathology, suggesting that a similar mechanism may underlie the increased risk for AD in men with low testosterone. In addition, DHT regulated synaptic plasticity in the hippocampus of mild cognitive impairment (MCI) SAMP8 mice and delayed the progression of disease to Alzheimer's dementia. In conclusion, androgen-based hormone therapy is a potentially useful strategy for preventing the progression of MCI in aging men. Androgens enhance synaptic markers (SYN, PSD95, and Drebrin), activate CREB, modulate the fundamental biology of synaptic structure, and lead to the structural changes of plasticity in the hippocampus, all of which result in improved cognitive function. PMID:27588067

  19. Spinal Cord Injury Impairs Neurogenesis and Induces Glial Reactivity in the Hippocampus.

    PubMed

    Jure, Ignacio; Pietranera, Luciana; De Nicola, Alejandro F; Labombarda, Florencia

    2017-03-13

    The incorporation of newborn neurons with increased synaptic remodeling and activity-dependent plasticity in the dentate gyrus enhances hippocampal-dependent learning performances. Astrocytes and microglial cells are components of the neurogenic niche and regulate neurogenesis under normal and neurophatological conditions leading to functional consequences for learning and memory. Although cognitive impairments were reported in patients after spinal cord injury (SCI), only few studies have considered remote changes in brain structures which are not related with sensory and motor cortex. Thus, we examined neurogenesis and glial reactivity by stereological assessment in dentate gyrus sub-regions after three different intensities of thoracic spinal cord compression in rats. Sixty days after injury we observed a decrease in the Basso-Bresnahan-Beattie locomotor scale scores, rotarod performance and volume of spare tissue that correlated with the severity of the compression. Regarding the hippocampus, we observed that neurogenesis and hilar neurons were reduced after severe SCI, while only neurogenesis decreased in the moderately injured group. In addition, severe SCI induced reactive microglia and astrogliosis in all dentate gyrus sub-regions. Furthermore, the density of reactive microglia increased in the hilus whereas astrogliosis developed in the molecular layer after moderate SCI. No changes were observed in the mildly injured rats. These results suggest glial response and neurogenesis are associated with injury intensity. Interestingly, hippocampal neurogenesis is more sensitive to SCI than astrocytes or microglia reaction, as moderate injury impairs the generation of new neurons without changing glial response in the subgranular zone.

  20. Functional-structural degeneration in dorsal and ventral attention systems for Alzheimer's disease, amnestic mild cognitive impairment.

    PubMed

    Qian, Shaowen; Zhang, Zhaoyan; Li, Bo; Sun, Gang

    2015-12-01

    Growing evidence of attention related failures in patients with amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD) has already been proposed by previous studies. However, previous studies lacked of systematic investigation on the functional and structural substrates for attention function for patients with AD and aMCI. In this work, we investigated the functional connectivity and gray matter density in dorsal and ventral attention networks (DAN, VAN) of normal participants (n = 15) and patients with aMCI (n = 12) and AD (n = 16) by applying group independent component analysis (ICA) and voxel-based morphometry (VBM) analysis. Using ICA, we extracted the functional patterns of DAN and VAN which are respectively responsible for the "top-down" attention process and "bottom-up" process. One-way analysis of variance (ANOVA) revealed significant group-differed functional connectivity in bilateral frontal eye fields (FEF) area and intraparietal sulcus (IPS) area, as well as posterior cingulate cortex and precuneus in the dorsal system. With regard to the ventral system, group-effects were significantly focused in right orbital superior/middle frontal gyrus, right inferior parietal lobule, angular gyrus, and supramarginal gyrus around the temporal-parietal junction area. Post hoc cluster-level comparisons revealed totally impaired functional substrates for both attentional networks for patients with AD, whereas selectively impaired attention systems for patients with aMCI with impaired functional patent of DAN but preserved functional pattern of VAN. Correspondingly, VBM analysis revealed gray matter loss in right ventral and dorsal frontal cortex was in the AD group, whereas preserved gray matter density was in aMCI, even a little extent of expansion of gray matter density in several participants. Using multivariate regression analysis we found discrepant couplings of functional-structural degenerations between both patient groups

  1. Dorsal column sensory axons degenerate due to impaired microvascular perfusion after spinal cord injury in rats

    PubMed Central

    Muradov, Johongir M.; Ewan, Eric E.; Hagg, Theo

    2013-01-01

    The mechanisms contributing to axon loss after spinal cord injury (SCI) are largely unknown but may involve microvascular loss as we have previously suggested. Here, we used a mild contusive injury (120 kdyn IH impactor) at T9 in rats focusing on ascending primary sensory dorsal column axons, anterogradely traced from the sciatic nerves. The injury caused a rapid and progressive loss of dorsal column microvasculature and oligodendrocytes at the injury site and penumbra and a ~70% loss of the sensory axons, by 24 hours. To model the microvascular loss, focal ischemia of the T9 dorsal columns was achieved via phototoxic activation of intravenously injected rose bengal. This caused an ~53% loss of sensory axons and an ~80% loss of dorsal column oligodendrocytes by 24 hours. Axon loss correlated with the extent and axial length of microvessel and oligodendrocyte loss along the dorsal column. To determine if oligodendrocyte loss contributes to axon loss, the glial toxin ethidium bromide (EB; 0.3 µg/µl) was microinjected into the T9 dorsal columns, and resulted in an ~88% loss of dorsal column oligodendrocytes and an ~56% loss of sensory axons after 72 hours. EB also caused an ~72% loss of microvessels. Lower concentrations of EB resulted in less axon, oligodendrocyte and microvessel loss, which were highly correlated (R2 = 0.81). These data suggest that focal spinal cord ischemia causes both oligodendrocyte and axon degeneration, which are perhaps linked. Importantly, they highlight the need of limiting the penumbral spread of ischemia and oligodendrocyte loss after SCI in order to protect axons. PMID:23978615

  2. Dorsal column sensory axons degenerate due to impaired microvascular perfusion after spinal cord injury in rats.

    PubMed

    Muradov, Johongir M; Ewan, Eric E; Hagg, Theo

    2013-11-01

    The mechanisms contributing to axon loss after spinal cord injury (SCI) are largely unknown but may involve microvascular loss as we have previously suggested. Here, we used a mild contusive injury (120 kdyn IH impactor) at T9 in rats focusing on ascending primary sensory dorsal column axons, anterogradely traced from the sciatic nerves. The injury caused a rapid and progressive loss of dorsal column microvasculature and oligodendrocytes at the injury site and penumbra and an ~70% loss of the sensory axons by 24 h. To model the microvascular loss, focal ischemia of the T9 dorsal columns was achieved via phototoxic activation of intravenously injected rose bengal. This caused an ~53% loss of sensory axons and an ~80% loss of dorsal column oligodendrocytes by 24 h. Axon loss correlated with the extent and axial length of microvessel and oligodendrocyte loss along the dorsal column. To determine if oligodendrocyte loss contributes to axon loss, the glial toxin ethidium bromide (EB; 0.3 μg/μl) was microinjected into the T9 dorsal columns, and resulted in an ~88% loss of dorsal column oligodendrocytes and an ~56% loss of sensory axons after 72 h. EB also caused an ~75% loss of microvessels. Lower concentrations of EB resulted in less axon, oligodendrocyte and microvessel loss, which were highly correlated (R(2) = 0.81). These data suggest that focal spinal cord ischemia causes both oligodendrocyte and axon degeneration, which are perhaps linked. Importantly, they highlight the need of limiting the penumbral spread of ischemia and oligodendrocyte loss after SCI in order to protect axons. © 2013.

  3. Coital Urinary Incontinence Induced by Impairment of the Dorsal Nerve of the Clitoris in Rats.

    PubMed

    Cruz, Yolanda; Juárez, Raúl; Medel, Alfonso; Corona-Quintanilla, Dora Luz; Pacheco, Pablo; Juárez, Margarita

    2016-02-01

    We determined the effect of chronic bilateral neurectomy of the dorsal nerve of the clitoris on urinary parameters and sexual behavior of conscious female rats. A total of 18 anesthetized virgin female Wistar rats were used in this study, including 11 that underwent bilateral neurectomy of the dorsal nerve of the clitoris and 7 that underwent sham surgery. Urinary parameters were determined in awake animals preoperatively, and 3 and 10 days postoperatively. Sexual behavior was tested 14 days postoperatively to determine whether the females expelled urine during sexual encounters. After male ejaculation the females were anesthetized with urethane to record external urethral sphincter electromyogram activity in response to clitoris, perigenital skin and vaginal stimulation. Neurectomy was corroborated anatomically. Sham surgery did not significantly modify urinary parameter values. However, bilateral neurectomy of the dorsal nerve of the clitoris significantly increased voiding frequency and voiding duration (p <0.05). It did not significantly affect the flow rate, voided volume or voiding interval. Of females that underwent bilateral neurectomy of the dorsal nerve of the clitoris 67% expelled urine just after male ejaculation. These results suggest that the pudendal nerve is an important neural pathway in the convergence and crosstalk of female urogenital neural circuits, and genital deafferentation may be a causal factor of coital urinary incontinence. Rats with bilateral transection of the dorsal nerve of the clitoris may serve as an animal model of coital incontinence. Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  4. Electromagnetic radiation (Wi-Fi) and epilepsy induce calcium entry and apoptosis through activation of TRPV1 channel in hippocampus and dorsal root ganglion of rats.

    PubMed

    Ghazizadeh, Vahid; Nazıroğlu, Mustafa

    2014-09-01

    Incidence rates of epilepsy and use of Wi-Fi worldwide have been increasing. TRPV1 is a Ca(2+) permeable and non-selective channel, gated by noxious heat, oxidative stress and capsaicin (CAP). The hyperthermia and oxidant effects of Wi-Fi may induce apoptosis and Ca(2+) entry through activation of TRPV1 channel in epilepsy. Therefore, we tested the effects of Wi-Fi (2.45 GHz) exposure on Ca(2+) influx, oxidative stress and apoptosis through TRPV1 channel in the murine dorsal root ganglion (DRG) and hippocampus of pentylentetrazol (PTZ)-induced epileptic rats. Rats in the present study were divided into two groups as controls and PTZ. The PTZ groups were divided into two subgroups namely PTZ + Wi-Fi and PTZ + Wi-Fi + capsazepine (CPZ). The hippocampal and DRG neurons were freshly isolated from the rats. The DRG and hippocampus in PTZ + Wi-Fi and PTZ + Wi-Fi + CPZ groups were exposed to Wi-Fi for 1 hour before CAP stimulation. The cytosolic free Ca(2+), reactive oxygen species production, apoptosis, mitochondrial membrane depolarization, caspase-3 and -9 values in hippocampus were higher in the PTZ group than in the control although cell viability values decreased. The Wi-Fi exposure induced additional effects on the cytosolic Ca(2+) increase. However, pretreatment of the neurons with CPZ, results in a protection against epilepsy-induced Ca(2+) influx, apoptosis and oxidative damages. In results of whole cell patch-clamp experiments, treatment of DRG with Ca(2+) channel antagonists [thapsigargin, verapamil + diltiazem, 2-APB, MK-801] indicated that Wi-Fi exposure induced Ca(2+) influx via the TRPV1 channels. In conclusion, epilepsy and Wi-Fi in our experimental model is involved in Ca(2+) influx and oxidative stress-induced hippocampal and DRG death through activation of TRPV1 channels, and negative modulation of this channel activity by CPZ pretreatment may account for the neuroprotective activity against oxidative stress.

  5. Lidocaine Injections Targeting CA3 Hippocampus Impair Long-Term Spatial Memory and Prevent Learning-Induced Mossy Fiber Remodeling

    PubMed Central

    Holahan, Matthew R.; Routtenberg, Aryeh

    2010-01-01

    Learning a spatial location induces remodeling of the mossy fiber terminal field (MFTF) in the CA3 subfield of the dorsal hippocampus (Holahan et al., 2006; Ramirez-Amaya et al., 2001; Rekart et al., 2007a). These fibers appear to grow from the stratum lucidum (SL) into distal stratum oriens (dSO). Is this axonal growth dependent on ‘repeated and persistent’ neural activity in the CA3 region during training? To address this issue, we targeted local inactivation of the MFTF region in a post-training, consolidation paradigm. Male Wistar rats, bilaterally implanted with chronic indwelling cannulae aimed at the MFTF CA3 region, were trained on a hidden platform water maze task (10 trials per day for 5 days). Immediately after the 10th trial on each training day, rats were injected with lidocaine (4% w/V; 171 mM; n = 7) or phosphate-buffered saline (PBS; n = 7). Behavioral measures of latency, path length and thigmotaxis were recorded, as was directional heading. A retention test (probe trial) was given 7 days after the last training day and brains were subsequently processed for MFTF distribution (Timm’s stain) and cannula location. Lidocaine treatment was found to block the learning-associated structural remodeling of the MFTF that was reported previously and observed in the PBS-injected controls. During training, the lidocaine group showed elevated latencies and a misdirected heading to locate the platform on the first trial of each training day. On the 7-day retention probe trial, the lidocaine-injected group showed poor retention indicated by the absence of a search bias in the area where the platform had been located during training. These data suggest that reduction of neuronal activity in the CA3 region impairs long-term storage of spatial information. As this was associated with reduced MFTF structural remodeling, it provides initial anatomical and behavioral evidence for an activity – dependent, presynaptic growth model of memory. PMID:20865723

  6. Myelin injury induces axonal transport impairment but not AD-like pathology in the hippocampus of cuprizone-fed mice

    PubMed Central

    Sun, Junjun; Zhou, Hong; Bai, Feng; Ren, Qingguo; Zhang, Zhijun

    2016-01-01

    Both multiple sclerosis (MS) and Alzheimer's disease (AD) are progressive neurological disorders with myelin injury and memory impairment. However, whether myelin impairment could cause AD-like neurological pathology remains unclear. To explore neurological pathology following myelin injury, we assessed cognitive function, the expression of myelin proteins, axonal transport-associated proteins, axonal structural proteins, synapse-associated proteins, tau and beta amyloid and the status of neurons, using the cuprizone mouse model of demyelination. We found the mild impairment of learning ability in cuprizone-fed mice and the decreased expression of myelin basic protein (MBP) in the hippocampus. And anti-LINGO-1 improved learning ability and partly restored MBP level. Furthermore, we also found kinesin light chain (KLC), neurofilament light chain (NFL) and neurofilament heavy chain (NF200) were declined in demyelinated hippocampus, which could be partly improved by treatment with anti-LINGO-1. However, we did not observe the increased expression of beta amyloid, hyperphosphorylation of tau and loss of neurons in demyelinated hippocampus. Our results suggest that demyelination might lead to the impairment of neuronal transport, but not cause increased level of hyperphosphorylated tau and beta amyloid. Our research demonstrates remyelination might be an effective pathway to recover the function of neuronal axons and cognition in MS. PMID:27129150

  7. Methylphenidate Decreases ATP Levels and Impairs Glutamate Uptake and Na(+),K(+)-ATPase Activity in Juvenile Rat Hippocampus.

    PubMed

    Schmitz, Felipe; Pierozan, Paula; Rodrigues, André F; Biasibetti, Helena; Grings, Mateus; Zanotto, Bruna; Coelho, Daniella M; Vargas, Carmen R; Leipnitz, Guilhian; Wyse, Angela T S

    2016-11-14

    The study of the long-term neurological consequences of early exposure with methylphenidate (MPH) is very important since this psychostimulant has been widely misused by children and adolescents who do not meet full diagnostic criteria for ADHD. The aim of this study was to examine the effect of early chronic exposure with MPH on amino acids profile, glutamatergic and Na(+),K(+)-ATPase homeostasis, as well as redox and energy status in the hippocampus of juvenile rats. Wistar male rats received intraperitoneal injections of MPH (2.0 mg/kg) or saline solution (controls), once a day, from the 15th to the 45th day of age. Results showed that MPH altered amino acid profile in the hippocampus, decreasing glutamine levels. Glutamate uptake and Na(+),K(+)-ATPase activity were decreased after chronic MPH exposure in the hippocampus of rats. No changes were observed in the immunocontents of glutamate transporters (GLAST and GLT-1), and catalytic subunits of Na(+),K(+)-ATPase (α1, α2, and α3), as well as redox status. Moreover, MPH provoked a decrease in ATP levels in the hippocampus of chronically exposed rats, while citrate synthase, succinate dehydrogenase, respiratory chain complexes activities (II, II-III, and IV), as well as mitochondrial mass and mitochondrial membrane potential were not altered. Taken together, our results suggest that chronic MPH exposure at early age impairs glutamate uptake and Na(+),K(+)-ATPase activity probably by decreasing in ATP levels observed in rat hippocampus.

  8. Interactions of the dorsal hippocampus, medial prefrontal cortex and nucleus accumbens in formation of fear memory: difference in inhibitory avoidance learning and contextual fear conditioning.

    PubMed

    Yang, Fang-Chi; Liang, K C

    2014-07-01

    Learning active or reactive responses to fear involves different brain circuitry. This study examined how the nuclus accumbens (NAc), dorsal hippocampus (DH) and medial prefrontal cortex (mPFC) may interact in memory processing for these two kinds of responses. Male Wistar rats with cannulae implanted in these areas were trained on a contextual fear conditioning or inhibitory avoidance task that respectively engaged a reactive or active response to fear in the test. Immediately after training, a memory modulating factor released by stress, norepinephrine (NE), was infused into one region and 4% lidocaine into another to examine if an upstream activation effect could be blocked by the downstream suppression. Retention tested 1 day later showed that in both tasks posttraining infusion of NE at different doses into either the DH or mPFC enhanced retention but the enhancement was blocked by concurrent infusion of lidocaine into the other region, suggesting reliance of the effect on functional integrity of both regions. Further, posttraining intra-NAc lidocaine infusion attenuated memory enhancement of NE infused to the DH or mPFC in the inhibitory avoidance task but did not do so in contextual fear conditioning. These results suggest that NE regulation of memory formation for the reactive and active responses to fear may rely on distinct interactions among the DH, mPFC and NAc. Copyright © 2014 Elsevier Inc. All rights reserved.

  9. Identification of a sustained neurogenic zone at the dorsal surface of the adult mouse hippocampus and its regulation by the chemokine SDF-1.

    PubMed

    Belmadani, Abdelhak; Ren, Dongjun; Bhattacharyya, Bula J; Rothwangl, Katharina B; Hope, Thomas J; Perlman, Harris; Miller, Richard J

    2015-11-01

    We identified a previously unknown neurogenic region at the dorsal surface of the hippocampus; (the "subhippocampal zone," SHZ) in the adult brain. Using a reporter mouse in which SHZ cells and their progeny could be traced through the expression of EGFP under the control of the CXCR4 chemokine receptor promoter we observed the presence of a pool of EGFP expressing cells migrating in direction of the dentate gyrus (DG), which is maintained throughout adulthood. This population appeared to originate from the SHZ where cells entered a caudal migratory stream (aCMS) that included the fimbria, the meninges and the DG. Deletion of CXCR4 from neural stem cells (NSCs) or neuroinflammation resulted in the appearance of neurons in the DG, which were the result of migration of NSCs from the SHZ. Some of these neurons were ectopically placed. Our observations indicate that the SHZ is a neurogenic zone in the adult brain through migration of NSCs in the aCMS. Regulation of CXCR4 signaling in these cells may be involved in repair of the DG and may also give rise to ectopic granule cells in the DG in the context of neuropathology.

  10. Identification of a Sustained Neurogenic Zone at the Dorsal Surface of the Adult Mouse Hippocampus and Its Regulation by the Chemokine SDF-1

    PubMed Central

    Belmadani, Abdelhak; Ren, Dongjun; Bhattacharyya, Bula J.; Rothwangl, Katharina B.; Hope, Thomas J.; Perlman, Harris; Miller, Richard J.

    2015-01-01

    We identified a previously unknown neurogenic region at the dorsal surface of the hippocampus; (the “subhippocampal zone,” SHZ) in the adult brain. Using a reporter mouse in which SHZ cells and their progeny could be traced through the expression of EGFP under the control of the CXCR4 chemokine receptor promoter we observed the presence of a pool of EGFP expressing cells migrating in direction of the dentate gyrus (DG), which is maintained throughout adulthood. This population appeared to originate from the SHZ where cells entered a caudal migratory stream (aCMS) that included the fimbria, the meninges and the DG. Deletion of CXCR4 from neural stem cells (NSCs) or neuroinflammation resulted in the appearance of neurons in the DG, which were the result of migration of NSCs from the SHZ. Some of these neurons were ectopically placed. Our observations indicate that the SHZ is a neurogenic zone in the adult brain through migration of NSCs in the aCMS. Regulation of CXCR4 signaling in these cells may be involved in repair of the DG and may also give rise to ectopic granule cells in the DG in the context of neuropathology. PMID:25656357

  11. Impaired hippocampal-dependent learning and functional abnormalities in the hippocampus in mice lacking serotonin1A receptors

    PubMed Central

    Sarnyai, Zoltán; Sibille, Etienne L.; Pavlides, Constantine; Fenster, Robert J.; McEwen, Bruce S.; Tóth, Miklós

    2000-01-01

    The hippocampus is a major limbic target of the brainstem serotonergic neurons that modulate fear, anxiety, and learning through postsynaptic serotonin1A receptors (5-HT1A receptors). Because chronic stress selectively down-regulates the 5-HT1A receptors in the hippocampus, we hypothesized that mice lacking these receptors may exhibit abnormalities reminiscent of symptoms of stress-related psychiatric disorders. In particular, a hippocampal deficit in the 5-HT1A receptor could contribute to the cognitive abnormalities often seen in these disorders. To test whether a deficit in 5-HT1A receptors impairs hippocampus-related functions, we studied hippocampal-dependent learning and memory, synaptic plasticity in the hippocampus, and limbic neuronal excitability in 5-HT1A-knockout (KO) mice. 5-HT1A-KO animals showed a deficit in hippocampal-dependent learning and memory tests, such as the hidden platform (spatial) version of the Morris water maze and the delayed version of the Y maze. The performance of KO mice was not impaired in nonhippocampal memory tasks such as the visible platform (nonspatial) version of the Morris water maze, the immediate version of the Y maze, and the spontaneous-alternation test of working memory. Furthermore, paired-pulse facilitation in the dentate gyrus of the hippocampus was impaired in 5-HT1A-KO mice. Finally, 5-HT1A-KO mice, as compared with wild-type animals, displayed higher limbic excitability manifested as lower seizure threshold and higher lethality in response to kainic acid administration. These results demonstrate that 5-HT1A receptors are required for maintaining normal hippocampal functions and implicate a role for the 5-HT1A receptor in hippocampal-related symptoms, such as cognitive disturbances, in stress-related disorders. PMID:11121072

  12. Loss of molars early in life develops behavioral lateralization and impairs hippocampus-dependent recognition memory

    PubMed Central

    2014-01-01

    mesocorticolimbic dopaminergic systems to impair the cognitive functions of selective attention and recognition memory in the prefrontal cortex and the hippocampus. PMID:24387332

  13. Hyperammonemia induces glial activation, neuroinflammation and alters neurotransmitter receptors in hippocampus, impairing spatial learning: reversal by sulforaphane.

    PubMed

    Hernández-Rabaza, Vicente; Cabrera-Pastor, Andrea; Taoro-González, Lucas; Malaguarnera, Michele; Agustí, Ana; Llansola, Marta; Felipo, Vicente

    2016-02-16

    Patients with liver cirrhosis and minimal hepatic encephalopathy (MHE) show mild cognitive impairment and spatial learning dysfunction. Hyperammonemia acts synergistically with inflammation to induce cognitive impairment in MHE. Hyperammonemia-induced neuroinflammation in hippocampus could contribute to spatial learning impairment in MHE. Two main aims of this work were: (1) to assess whether chronic hyperammonemia increases inflammatory factors in the hippocampus and if this is associated with microglia and/or astrocytes activation and (2) to assess whether hyperammonemia-induced neuroinflammation in the hippocampus is associated with altered membrane expression of glutamate and GABA receptors and spatial learning impairment. There are no specific treatments for cognitive alterations in patients with MHE. A third aim was to assess whether treatment with sulforaphane enhances endogenous the anti-inflammatory system, reduces neuroinflammation in the hippocampus of hyperammonemic rats, and restores spatial learning and if normalization of receptor membrane expression is associated with learning improvement. We analyzed the following in control and hyperammonemic rats, treated or not with sulforaphane: (1) microglia and astrocytes activation by immunohistochemistry, (2) markers of pro-inflammatory (M1) (IL-1β, IL-6) and anti-inflammatory (M2) microglia (Arg1, YM-1) by Western blot, (3) membrane expression of GABA, AMPA, and NMDA receptors using the BS3 cross-linker, and (4) spatial learning using the radial maze. The results reported show that hyperammonemia induces astrocytes and microglia activation in the hippocampus, increasing pro-inflammatory cytokines IL-1β and IL-6. This is associated with altered membrane expression of AMPA, NMDA, and GABA receptors which would be responsible for altered neurotransmission and impairment of spatial learning in the radial maze. Treatment with sulforaphane promotes microglia differentiation from pro-inflammatory M1 to anti

  14. The BDNF Val66Met polymorphism impairs NMDA receptor-dependent synaptic plasticity in the hippocampus.

    PubMed

    Ninan, Ipe; Bath, Kevin G; Dagar, Karishma; Perez-Castro, Rosalia; Plummer, Mark R; Lee, Francis S; Chao, Moses V

    2010-06-30

    The Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene results in a defect in regulated release of BDNF and affects episodic memory and affective behaviors. However, the precise role of the BDNF Val66Met polymorphism in hippocampal synaptic transmission and plasticity has not yet been studied. Therefore, we examined synaptic properties in the hippocampal CA3-CA1 synapses of BDNF(Met/Met) mice and matched wild-type mice. Although basal glutamatergic neurotransmission was normal, both young and adult mice showed a significant reduction in NMDA receptor-dependent long-term potentiation. We also found that NMDA receptor-dependent long-term depression was decreased in BDNF(Met/Met) mice. However, mGluR-dependent long-term depression was not affected by the BDNF Val66Met polymorphism. Consistent with the NMDA receptor-dependent synaptic plasticity impairment, we observed a significant decrease in NMDA receptor neurotransmission in the CA1 pyramidal neurons of BDNF(Met/Met) mice. Thus, these results show that the BDNF Val66Met polymorphism has a direct effect on NMDA receptor transmission, which may account for changes in synaptic plasticity in the hippocampus.

  15. Trajectories of peripheral interleukin-6, structure of the hippocampus, and cognitive impairment over 14 years in older adults

    PubMed Central

    Metti, Andrea L.; Aizenstein, Howard; Yaffe, Kristine; Boudreau, Robert M.; Newman, Anne; Launer, Lenore; Gianaros, Peter J.; Lopez, Oscar L.; Saxton, Judith; Ives, Diane G.; Kritchevsky, Stephen; Vallejo, Abbe N.; Rosano, Caterina

    2015-01-01

    We aimed to investigate if trajectory components (baseline level, slope and variability) of peripheral IL-6 over time were related to cognitive impairment and smaller hippocampal volume, and if hippocampal volume explained the associations between IL-6 and cognitive impairment. Multivariable regression models were used to test the association between IL-6 trajectory components with change in neuroimaging measures of the hippocampus, and with cognitive impairment among 135 older adults (70–79 years at baseline) from the Healthy Brain Project over 14 years. IL-6 variability was positively associated with cognitive impairment (OR = 5.86, 95% CI:1.24, 27.61) and with greater decrease per year of gray matter volume of the hippocampus (β=−0.008, SE=0.004, p=0.03). After adjustment for hippocampal volume, the odds ratio of cognitive impairment decreased for each unit of IL-6 variability, and confidence intervals widened (OR=4.36, 95% CI: 0.67, 28.29). Neither baseline levels nor slopes of IL-6 were related to cognitive impairment or hippocampal volume. We believe this has potential clinical and public health implications by suggesting adults with stable levels of peripheral IL-6 may be better targets for intervention studies for slowing or preventing cognitive decline. PMID:26279115

  16. Hippocampus-dependent spatial memory impairment due to molar tooth loss is ameliorated by an enriched environment.

    PubMed

    Kondo, Hiroko; Kurahashi, Minori; Mori, Daisuke; Iinuma, Mitsuo; Tamura, Yasuo; Mizutani, Kenmei; Shimpo, Kan; Sonoda, Shigeru; Azuma, Kagaku; Kubo, Kin-ya

    2016-01-01

    Teeth are crucial, not only for mastication, but for overall nutrition and general health, including cognitive function. Aged mice with chronic stress due to tooth loss exhibit impaired hippocampus-dependent learning and memory. Exposure to an enriched environment restores the reduced hippocampal function. Here, we explored the effects of an enriched environment on learning deficits and hippocampal morphologic changes in aged senescence-accelerated mouse strain P8 (SAMP8) mice with tooth loss. Eight-month-old male aged SAMP8 mice with molar intact or with molars removed were housed in either a standard environment or enriched environment for 3 weeks. The Morris water maze was performed for spatial memory test. The newborn cell proliferation, survival, and differentiation in the hippocampus were analyzed using 5-Bromodeoxyuridine (BrdU) immunohistochemical method. The hippocampal brain-derived neurotrophic factor (BDNF) levels were also measured. Mice with upper molars removed (molarless) exhibited a significant decline in the proliferation and survival of newborn cells in the dentate gyrus (DG) as well as in hippocampal BDNF levels. In addition, neuronal differentiation of newly generated cells was suppressed and hippocampus-dependent spatial memory was impaired. Exposure of molarless mice to an enriched environment attenuated the reductions in the hippocampal BDNF levels and neuronal differentiation, and partially improved the proliferation and survival of newborn cells, as well as the spatial memory ability. These findings indicated that an enriched environment could ameliorate the hippocampus-dependent spatial memory impairment induced by molar tooth loss. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. Dynamic association of epigenetic H3K4me3 and DNA 5hmC marks in the dorsal hippocampus and anterior cingulate cortex following reactivation of a fear memory.

    PubMed

    Webb, William M; Sanchez, Richard G; Perez, Gabriella; Butler, Anderson A; Hauser, Rebecca M; Rich, Megan C; O'Bierne, Aidan L; Jarome, Timothy J; Lubin, Farah D

    2017-02-20

    Epigenetic mechanisms such as DNA methylation and histone methylation are critical regulators of gene transcription changes during memory consolidation. However, it is unknown how these epigenetic modifications coordinate control of gene expression following reactivation of a previously consolidated memory. Here, we found that retrieval of a recent contextual fear conditioned memory increased global levels of H3 lysine 4-trimethylation (H3K4me3) and DNA 5-hydroxymethylation (5hmC) in area CA1 of the dorsal hippocampus. Further experiments revealed increased levels of H3K4me3 and DNA 5hmC within a CpG-enriched coding region of the Npas4, but not c-fos, gene. Intriguingly, retrieval of a 30-day old memory increased H3K4me3 and DNA 5hmC levels at a CpG-enriched coding region of c-fos, but not Npas4, in the anterior cingulate cortex, suggesting that while these two epigenetic mechanisms co-occur following the retrieval of a recent or remote memory, their gene targets differ depending on the brain region. Additionally, we found that in vivo siRNA-mediated knockdown of the H3K4me3 methyltransferase Mll1 in CA1 abolished retrieval-induced increases in DNA 5hmC levels at the Npas4 gene, suggesting that H3K4me3 couples to DNA 5hmC mechanisms. Consistent with this, loss of Mll1 prevented retrieval-induced increases in Npas4 mRNA levels in CA1 and impaired fear memory. Collectively, these findings suggest an important link between histone methylation and DNA hydroxymethylation mechanisms in the epigenetic control of de novo gene transcription triggered by memory retrieval.

  18. Developmental neurotoxicity of the hippocampus following in utero exposure to methylmercury: impairment in cell signaling.

    PubMed

    Heimfarth, Luana; Delgado, Jeferson; Mignori, Moara Rodrigues; Gelain, Daniel Pens; Moreira, José Cláudio Fonseca; Pessoa-Pureur, Regina

    2017-08-18

    In this study, we assessed some hippocampal signaling cascades and behavioral impairments in 30-day-old rat pups prenatally exposed to methylmercury (MeHg). Pregnant rats were exposed to 1.0 or 2.0 mg/kg MeHg by gavage in alternated days from gestational day 5 until parturition. We found increased anxiety-like and decreased exploration behavior evaluated by open field test and deficit of both short- and long-term memories by novel object recognition task, respectively, in MeHg-treated pups. Downregulated PI3K/Akt/mTOR pathway and activated/hypophosphorylated (Ser9) GSK3β in MeHg-treated pups could be upstream of hyperphosphorylated Tau (Ser396) destabilizing microtubules and contributing to neural dysfunction in the hippocampus of these rats. Hyperphosphorylated/activated p38MAPK and downregulated phosphoErk1/2 support a role for mitogen-activated protein kinase (MAPK) cascade on MeHg neurotoxicity. Decreased receptor of advanced glycation end products (RAGE) immunocontent supports the assumption that downregulated RAGE/Erk1/2 pathway could be involved in hypophosphorylated lysine/serine/proline (KSP) repeats on neurofilament subunits and disturbed axonal transport. Downregulated myelin basic protein (MBP), the major myelin protein, is compatible with dysmyelination and neurofilament hypophosphorylation. Increased glial fibrillary acidic protein (GFAP) levels suggest reactive astrocytes, and active apoptotic pathways BAD/BCL-2, BAX/BCL-XL, and caspase 3 suggest cell death. Taken together, our findings get light on important signaling mechanisms that could underlie the behavioral deficits in 30-day-old pups prenatally exposed to MeHg.

  19. Involvement of GABA(B) receptors of the dorsal hippocampus on the acquisition and expression of morphine-induced place preference in rats.

    PubMed

    Zarrindast, Mohammad-Reza; Massoudi, Roohollah; Sepehri, Houri; Rezayof, Ameneh

    2006-01-30

    In the present study, effects of intra-hippocampal CA1 (intra-CA1) injections of GABA(B) receptor agonist and antagonist on the acquisition and expression of morphine-induced place preference in male Wistar rats have been investigated. Subcutaneous administration of different doses of morphine sulphate (0.5-6 mg/kg) produced a dose-dependent conditioned place preference (CPP). Using a 3-day schedule of conditioning, it was found that the GABA(B) receptor agonist, baclofen (0.5-2 microg/rat; intra-CA1), or the GABA(B) receptor antagonist, phaclofen (1-3 microg/rat; intra-CA1), did not produce a significant place preference or place aversion. Intra-CA1 administration of baclofen (1 and 2 microg/rat; intra-CA1) decreased the acquisition of CPP induced by morphine (3 mg/kg; s.c.). On the other hand, intra-CA1 injection of phaclofen (1 and 2 microg/rat; intra-CA1) in combination with a lower dose of morphine (1 mg/kg) elicited a significant CPP. The response of baclofen (2 microg/rat; intra-CA1) was reversed by phaclofen (4 and 6 microg/rat; intra-CA1). Furthermore, intra-CA1 administration of baclofen but not phaclofen before testing significantly decreased the expression of morphine (3 mg/kg; s.c.)-induced place preference. Baclofen or phaclofen injections had no effects on locomotor activity on the testing sessions. It is concluded that the GABA(B) receptors in dorsal hippocampus may play an active role in morphine reward.

  20. Activation of phasic pontine-wave generator in the rat: a mechanism for expression of plasticity-related genes and proteins in the dorsal hippocampus and amygdala

    PubMed Central

    Datta, Subimal; Li, Guangmu; Auerbach, Sanford

    2008-01-01

    A number of behavioral studies have emphasized the importance of interactions between the pontine-wave (P-wave) generator and the dorsal hippocampus (DH) in two-way active avoidance (TWAA) memory processing; however, the direct involvement of the P-wave generator in the TWAA training trial-induced molecular events in the DH and amygdala has not been systematically evaluated. Here we demonstrate that the TWAA learning training trials activate P-wave generator, and increase phosphorylation of CREB (pCREB) and expression of activity-regulated cytoskeletal-associated (Arc) protein, as well as messenger ribonucleic acid (mRNAs) of Arc, brain-derived nerve growth factor (BDNF) and early growth response-1 (Egr-1) in the DH and amygdala. Selective elimination of P-wave-generating cells abolished P-wave activity and suppressed TWAA learning training trial-induced expression of pCREB and Arc proteins and Arc, BDNF and Egr-1 mRNAs in the DH and amygdala. Following a session of TWAA training, all rats were equal in terms of time spent in wakefulness, slow-wave sleep and rapid eye movement (REM) sleep irrespective of P-wave lesions. The second set of experiments demonstrated that localized cholinergic stimulation of the P-wave generator increased expression of Arc, BDNF and Egr-1 mRNAs in the DH. Together, these findings provide the first direct evidence that activation of P-wave-generating cells is critically involved in the TWAA training trial-induced expression of plasticity-related genes in the DH and amygdala. These findings are discussed in relation to the role of P-wave generator activation for the REM sleep-dependent development and cognitive functions of the brain. PMID:18371081

  1. Differences in the Flexibility of Switching Learning Strategies and CREB Phosphorylation Levels in Prefrontal Cortex, Dorsal Striatum and Hippocampus in Two Inbred Strains of Mice

    PubMed Central

    Cho, Woo-Hyun; Han, Jung-Soo

    2016-01-01

    Flexibility in using different learning strategies was assessed in two different inbred strains of mice, the C57BL/6 and DBA/2 strains. Mice were trained sequentially in two different Morris water maze protocols that tested their ability to switch their learning strategy to complete a new task after first being trained in a different task. Training consisted either of visible platform trials (cued training) followed by subsequent hidden platform trials (place training) or the reverse sequence (place training followed by cued training). Both strains of mice showed equivalent performance in the type of training (cued or place) that they received first. However, C57BL/6 mice showed significantly better performances than DBA/2 mice following the switch in training protocols, irrespective of the order of training. After completion of the switched training session, levels of cAMP response element-binding protein (CREB) and phosphorylated CREB (pCREB) were measured in the hippocampus, striatum and prefrontal cortex of the mice. Prefrontal cortical and hippocampal pCREB levels differed by strain, with higher levels found in C57BL/6 mice than in DBA/2 mice. No strain differences were observed in the medial or lateral region of the dorsal striatum. These findings indicate that the engagement (i.e., CREB signaling) of relevant neural structures may vary by the specific demands of the learning strategy, and this is closely tied to differences in the flexibility of C57BL/6 and DBA/2 mice to switch their learning strategies when given a new task. PMID:27695401

  2. Differences in the Flexibility of Switching Learning Strategies and CREB Phosphorylation Levels in Prefrontal Cortex, Dorsal Striatum and Hippocampus in Two Inbred Strains of Mice.

    PubMed

    Cho, Woo-Hyun; Han, Jung-Soo

    2016-01-01

    Flexibility in using different learning strategies was assessed in two different inbred strains of mice, the C57BL/6 and DBA/2 strains. Mice were trained sequentially in two different Morris water maze protocols that tested their ability to switch their learning strategy to complete a new task after first being trained in a different task. Training consisted either of visible platform trials (cued training) followed by subsequent hidden platform trials (place training) or the reverse sequence (place training followed by cued training). Both strains of mice showed equivalent performance in the type of training (cued or place) that they received first. However, C57BL/6 mice showed significantly better performances than DBA/2 mice following the switch in training protocols, irrespective of the order of training. After completion of the switched training session, levels of cAMP response element-binding protein (CREB) and phosphorylated CREB (pCREB) were measured in the hippocampus, striatum and prefrontal cortex of the mice. Prefrontal cortical and hippocampal pCREB levels differed by strain, with higher levels found in C57BL/6 mice than in DBA/2 mice. No strain differences were observed in the medial or lateral region of the dorsal striatum. These findings indicate that the engagement (i.e., CREB signaling) of relevant neural structures may vary by the specific demands of the learning strategy, and this is closely tied to differences in the flexibility of C57BL/6 and DBA/2 mice to switch their learning strategies when given a new task.

  3. NMDA receptors in the medial prefrontal cortex and the dorsal hippocampus regulate methamphetamine-induced hyperactivity and extracellular amino acid release in mice.

    PubMed

    Han, Wenyan; Wang, Fangyang; Qi, Jia; Wang, Fang; Zhang, Lijia; Zhao, Siqi; Song, Ming; Wu, Chunfu; Yang, Jingyu

    2012-06-15

    The medial prefrontal cortex (mPFC) and the dorsal hippocampus (DHC) play significant roles in stimulant-induced neurobehavioral effects. Methamphetamine (MAP)-induced hyperactivity has been reported to be involved in the regulation of the glutamatergic system. The present study examined whether the glutamatergic and GABAergic systems in the mPFC and DHC were involved in MAP-induced hyperactivity in mice. A combined kainic acid (KA) or N-methyl-d-aspartate (NMDA) lesion and microdialysis technique targeting both the mPFC and DHC were used. The results showed that both KA- and NMDA-induced lesions of the mPFC facilitated MAP-induced hyperactivity, while neither KA- nor NMDA-induced lesions of the DHC had a similar effect. MAP increased the extracellular glutamate (Glu) levels in the mPFC and reduced Glu levels in the DHC. GABA levels in both of these regions were reduced. A KA or NMDA lesion of the mPFC inhibited the Glu reduction in the DHC, and the same lesion of the DHC inhibited the Glu increase in the mPFC induced by MAP. A NMDA lesion of the mPFC blocked GABA reduction in the DHC, but a lesion of DHC enhanced the GABA decrease in the mPFC induced by MAP. Furthermore, a NMDA lesion of DHC increased the vesicular glutamate transporter-2 (VGLUT2) expression in the mPFC following MAP-administration. These findings indicate that glutamatergic as well as GABAergic systems in these two regions are involved in MAP-induced hyperactivity. Moreover, there may be an inhibitory role in these two regions, especially mediated by NMDA receptors, in MAP-induced abnormal behavior and neurotransmission responses.

  4. Chronic restraint stress impairs neurogenesis and hippocampus-dependent fear memory in mice: possible involvement of a brain-specific transcription factor Npas4.

    PubMed

    Yun, Jaesuk; Koike, Hiroyuki; Ibi, Daisuke; Toth, Erika; Mizoguchi, Hiroyuki; Nitta, Atsumi; Yoneyama, Masanori; Ogita, Kiyokazu; Yoneda, Yukio; Nabeshima, Toshitaka; Nagai, Taku; Yamada, Kiyofumi

    2010-09-01

    Neurogenesis in the hippocampus occurs throughout life in a wide range of species and could be associated with hippocampus-dependent learning and memory. Stress is well established to seriously perturb physiological/psychological homeostasis and affect hippocampal function. In the present study, to investigate the effect of chronic restraint stress in early life on hippocampal neurogenesis and hippocampus-dependent memory, 3-week-old mice were subjected to restraint stress 6 days a week for 4 weeks. The chronic restraint stress significantly decreased the hippocampal volume by 6.3% and impaired hippocampal neurogenesis as indicated by the reduced number of Ki67-, 5-bromo-2'-deoxyuridine- and doublecortin-positive cells in the dentate gyrus. The chronic restraint stress severely impaired hippocampus-dependent contextual fear memory without affecting hippocampus-independent fear memory. The expression level of brain-specific transcription factor neuronal PAS domain protein 4 (Npas4) mRNA in the hippocampus was down-regulated by the restraint stress or by acute corticosterone treatment. Npas4 immunoreactivity was detected in progenitors, immature and mature neurons of the dentate gyrus in control and stressed mice. Our findings suggest that the chronic restraint stress decreases hippocampal neurogenesis, leading to an impairment of hippocampus-dependent fear memory in mice. Corticosterone-induced down-regulation of Npas4 expression may play a role in stress-induced impairment of hippocampal function.

  5. Sodium Arsenite-Induced Learning and Memory Impairment Is Associated with Endoplasmic Reticulum Stress-Mediated Apoptosis in Rat Hippocampus.

    PubMed

    Sun, Hongna; Yang, Yanmei; Shao, Hanwen; Sun, Weiwei; Gu, Muyu; Wang, Hui; Jiang, Lixin; Qu, Lisha; Sun, Dianjun; Gao, Yanhui

    2017-01-01

    Chronic arsenic exposure has been associated to cognitive deficits. However, mechanisms remain unknown. The present study investigated the neurotoxic effects of sodium arsenite in drinking water over different dosages and time periods. Based on results from the Morris water maze (MWM) and morphological analysis, an exposure to sodium arsenite could induce neuronal damage in the hippocampus, reduce learning ability, and accelerate memory impairment. Sodium arsenite significantly increased homocysteine levels in serum and brain. Moreover, sodium arsenite triggered unfolded protein response (UPR), leading to the phosphorylation of RNA-regulated protein kinase-like ER kinase (PERK) and eukaryotic translation initiation factor 2 subunit α (eIF2α), and the induction of activating transcription factor 4 (ATF4). Arsenite exposure also stimulated the expression of the endoplasmic reticulum (ER) stress markers, glucose-regulated protein 78 (GRP78), C/EBP homologous protein (CHOP) and the cleavage of caspase-12. Furthermore, exposure to arsenite enhanced apoptosis as demonstrated by expression of caspase-3 and TUNEL assay in the hippocampus. The results suggest that exposure to arsenite can significantly decrease learning ability and accelerate memory impairment. Potential mechanisms are related to enhancement of homocysteine and ER stress-induced apoptosis in the hippocampus.

  6. Uhrf2 deletion impairs the formation of hippocampus-dependent memory by changing the structure of the dentate gyrus.

    PubMed

    Chen, Xiao-Rong; Sun, Shi-Cheng; Teng, Shuai-Wen; Li, Liang; Bie, Yi-Fan; Yu, Hui; Li, Da-Li; Chen, Zhe-Yu; Wang, Yue

    2017-09-12

    Ubiquitin-like with PHD and ring finger domains 2 (Uhrf2) is distributed in many brain regions, including the cortex and hippocampus. Decreased Uhrf2 expression is involved in neurodegenerative disease. A recent study showed Uhrf2 deletion impaired spatial memory; however, the mechanism remains elusive. In our study, we determined that Uhrf2(+/-) and Uhrf2(-/-) mice had significant learning and memory deficiencies in contextual fear conditioning (CFC) and the novel place recognition test but not in the novel object recognition test. Interestingly, there were no changes in the Uhrf2 protein levels in the hippocampus of C57BL6 mice after CFC training, which suggests Uhrf2 in adult mice may not be related to the formation of CFC long-term memory. Based on Nissl staining, Uhrf2 deletion caused neuropathological changes specifically in the crest of the dentate gyrus (DG), such as cell swelling, a vague outline and confused boundary; however, no changes were identified in the medial prefrontal cortex (mPFC). Transmission electron microscope assay further indicated a series of abnormal ultrastructure changes in neurons and glia in the DG crest. These results suggested that Uhrf2 deletion selectively blocked the development of the DG crest and impaired hippocampus-dependent learning and memory. Our study will facilitate a better understanding of the role of Uhrf2 protein in the central nervous system.

  7. Impaired and spared cholinergic functions in the hippocampus after lesions of the medial septum/vertical limb of the diagonal band with 192 IgG-saporin.

    PubMed

    Chang, Qing; Gold, Paul E

    2004-01-01

    To lesion the cholinergic input to the hippocampus, rats received injections of 192 IgG-saporin into the medial septum/vertical limb of the diagonal band (MS/VDB). The lesions produced near-total loss of choline acetyltransferase (ChAT)-positive neurons in the MS/VDB. The loss was accompanied, however, by only partial decreases (to 40% of control levels) in acetylcholine (ACh) release in the hippocampus. Moreover, ACh release in the hippocampus increased when lesioned and control rats were tested on a spontaneous alternation task, indicating that there was significant residual cholinergic function in the hippocampus. The lesions were sufficient to impair spontaneous alternation scores. However, this impairment could be reversed by either systemic or intra-hippocampal injections of the indirect cholinergic agonist, physostigmine, providing additional evidence of residual and effective cholinergic functions in the hippocampus of lesioned rats. Moreover, systemic injections of physostigmine at doses that produced mild tremors in control rats led to more severe tremors in the lesioned rats, suggesting upregulation of cholinergic mechanisms after saporin lesions, likely in brain areas other than the hippocampus. Thus, these findings provide evidence for decreases in cholinergic input to the hippocampus accompanied by deficits on a spontaneous alternation tasks. The findings also provide evidence for considerable residual cholinergic input to the hippocampus after saporin lesions of the MS/VDB. Together, the results suggest that 192 IgG-saporin lesions of the MS/VDB, using methods often employed, do not fully remove septohippocampal cholinergic input to the hippocampus but are nonetheless sufficient to produce impairments on a task impaired by hippocampal lesions.

  8. Paradoxical (REM) Sleep Deprivation Causes a Large and Rapidly Reversible Decrease in Long-Term Potentiation, Synaptic Transmission, Glutamate Receptor Protein Levels, and ERK/MAPK Activation in the Dorsal Hippocampus

    PubMed Central

    Ravassard, Pascal; Pachoud, Bastien; Comte, Jean-Christophe; Mejia-Perez, Camila; Scoté-Blachon, Céline; Gay, Nadine; Claustrat, Bruno; Touret, Monique; Luppi, Pierre-Hervé; Salin, Paul Antoine

    2009-01-01

    Study Objectives: It has been shown that wake (W) and slow wave sleep (SWS) modulate synaptic transmission in neocortical projections. However the impact of paradoxical sleep (PS) quantities on synaptic transmission remains unknown. We examined whether PS modulated the excitatory transmission and expression of glutamate receptor subtypes and phosphorylated extracellular signal-regulated kinases (p-ERK1/2). Design: PS deprivation (PSD) was carried out with the multiple platforms method on adult male Sprague-Dawley rats. LTP, late-LTP, and synaptic transmission were studied in the dorsal and ventral hippocampus of controls, 75-h PSD and 150-min PS rebound (PSR). GluR1 and NR1 protein and mRNA expression were evaluated by western blot and real-time PCR. P-ERK1/2 level was quantified by western blot and immunohistochemistry. Measurement and Results: PSD decreased synaptic transmission and LTP selectively in dorsal CA1 and PSR rescued these deficits. PSD-induced synaptic modifications in CA1 were associated with a decrease in GluR1, NR1, and p-ERK1/2 levels in dorsal CA1 without change in GluR1 and NR1 mRNA expression. Regression analysis shows that LTP is positively correlated with both PS quantities and SWS episodes duration, whereas synaptic transmission and late-LTP are positively correlated with PS quantities and negatively correlated with SWS quantities. Conclusions: These findings unveil previously unrecognized roles of PSD on synaptic transmission and LTP in the dorsal, but not in the ventral, hippocampus. The fact that the decrease in protein expression of GluR1 and NR1 was not associated with a change in mRNA expression of these receptors suggests that a sleep-induced modulation of translational mechanisms occurs in dorsal CA1. Citation: Ravassard P; Pachoud B; Comte JC; Mejia-Perez C; Scoté-Blachon C; Gay N; Claustrat B; Touret M; Luppi PH; Salin PA. Paradoxical (REM) sleep deprivation causes a large and rapidly reversible decrease in long-term potentiation

  9. Sleep deprivation impairs Ca2+ expression in the hippocampus: ionic imaging analysis for cognitive deficiency with TOF-SIMS.

    PubMed

    Chang, Hung-Ming; Liao, Wen-Chieh; Sheu, Ji-Nan; Chang, Chun-Chao; Lan, Chyn-Tair; Mai, Fu-Der

    2012-06-01

    Sleep deprivation causes cognitive dysfunction in which impaired neuronal plasticity in hippocampus may underlie the molecular mechanisms of this deficiency. Considering calcium-mediated NMDA receptor subunit 1 (NMDAR1) and neuronal nitric oxide synthase (nNOS) activation plays an important role in the regulation of neuronal plasticity, the present study is aimed to determine whether total sleep deprivation (TSD) would impair calcium expression, together with injury of the neuronal plasticity in hippocampus. Adult rats subjected to TSD were processed for time-of-flight secondary ion mass spectrometry, NMDAR1 immunohistochemistry, nNOS biochemical assay, cytochrome oxidase histochemistry, and the Morris water maze learning test to detect ionic, neurochemical, bioenergetic as well as behavioral changes of neuronal plasticity, respectively. Results indicated that in normal rats, strong calcium signaling along with intense NMDAR1/nNOS expression were observed in hippocampal regions. Enhanced calcium imaging and neurochemical expressions corresponded well with strong bioenergetic activity and good performance of behavioral testing. However, following TSD, both calcium intensity and NMDAR1/nNOS expressions were significantly decreased. Behavioral testing also showed poor responses after TSD. As proper calcium expression is essential for maintaining hippocampal neuronal plasticity, impaired calcium expression would depress downstream NMDAR1-mediated nNOS activation, which might contribute to the initiation or development of TSD-related cognitive deficiency.

  10. Disruption of the direct perforant path input to the CA1 subregion of the dorsal hippocampus interferes with spatial working memory and novelty detection.

    PubMed

    Vago, David R; Kesner, Raymond P

    2008-06-03

    Subregional analyses of the hippocampus suggest CA1-dependent memory processes rely heavily upon interactions between the CA1 subregion and entorhinal cortex. There is evidence that the direct perforant path (pp) projection to CA1 is selectively modulated by dopamine while having little to no effect on the Schaffer collateral (SC) projection to CA1. The current study takes advantage of this pharmacological dissociation to demonstrate that local infusion of the non-selective dopamine agonist, apomorphine (10, 15 microg), into the CA1 subregion of awake animals produces impairments in working memory at intermediate (5 min), but not short-term (10 s) delays within a delayed non-match-to-place task on a radial arm maze. Sustained impairments were also found in a novel context with similar object-space relationships. Infusion of apomorphine into CA1 is also shown here to produce deficits in spatial, but not non-spatial novelty detection within an object exploration paradigm. In contrast, apomorphine produces no behavioral deficits when infused into the CA3 subregion or overlying cortex. These behavioral studies are supported by previous electrophysiological data that demonstrate local infusion of the same doses of apomorphine significantly modifies evoked responses in the distal dendrites of CA1 following angular bundle stimulation, but produces no significant effects in the proximal dendritic layer following stimulation of the SC. These results support a modulatory role for dopamine in EC-CA1, but not CA3-CA1 circuitry, and suggest the possibility of a fundamental role for EC-CA1 synaptic transmission in terms of detection of spatial novelty, and intermediate-term, but not short-term spatial working memory or object-novelty detection.

  11. The presenilin-1 familial Alzheimer disease mutant P117L impairs neurogenesis in the hippocampus of adult mice.

    PubMed

    Wen, Paul H; Hof, Patrick R; Chen, Xiaoping; Gluck, Karen; Austin, Gregory; Younkin, Steven G; Younkin, Linda H; DeGasperi, Rita; Gama Sosa, Miguel A; Robakis, Nikolaos K; Haroutunian, Vahram; Elder, Gregory A

    2004-08-01

    The functions of presenilin 1 (PS1) and how PS1 mutations cause familial Alzheimer's disease (FAD) are incompletely understood. PS1 expression is essential for neurogenesis during embryonic development and may also influence neurogenesis in adult brain. We examined how increasing PS1 expression or expressing an FAD mutant would affect neurogenesis in the adult hippocampus. A neuron-specific enolase (NSE) promoter was used to drive neuronal overexpression of either wild-type human PS1 or the FAD mutant P117L in transgenic mice, and the animals were studied under standard-housing conditions or after environmental enrichment. As judged by bromodeoxyuridine (BrdU) labeling, neural progenitor proliferation rate was mostly unaffected by increasing expression of either wild-type or FAD mutant PS1. However, in both housing conditions, the FAD mutant impaired the survival of BrdU-labeled neural progenitor cells leading to fewer new beta-III-tubulin-immunoreactive neurons being generated in FAD mutant animals during the 4-week postlabeling period. The effect was FAD mutant specific in that neural progenitor survival and differentiation in mice overexpressing wild-type human PS1 were similar to nontransgenic controls. Two additional lines of PS1 wild-type and FAD mutant transgenic mice showed similar changes indicating that the effects were not integration site-dependent. These studies demonstrate that a PS1 FAD mutant impairs new neuron production in adult hippocampus by decreasing neural progenitor survival. They also identify a new mechanism whereby PS1 FAD mutants may impair normal neuronal function and may have implications for the physiological functioning of the hippocampus in FAD.

  12. Effects of Chronic Scopolamine Treatment on Cognitive Impairments and Myelin Basic Protein Expression in the Mouse Hippocampus.

    PubMed

    Park, Joon Ha; Choi, Hyun Young; Cho, Jeong-Hwi; Kim, In Hye; Lee, Tae-Kyeong; Lee, Jae-Chul; Won, Moo-Ho; Chen, Bai Hui; Shin, Bich-Na; Ahn, Ji Hyeon; Tae, Hyun-Jin; Choi, Jung Hoon; Chung, Jin-Young; Lee, Choong-Hyun; Cho, Jun Hwi; Kang, Il Jun; Kim, Jong-Dai

    2016-08-01

    Myelin plays an important role in learning and memory, and degradation of myelin is a key feature in the pathogenesis of neurological disorders involving cognitive dysfunction. Myelin basic protein (MBP) is one of the most abundant structural proteins in myelin and is essential for myelin formation and compaction. In this study, we first examined changes in the distribution of MBP-immunoreactive myelinated fibers and MBP levels according to hippocampal subregion in mice following chronic systemic treatment with 1 mg/kg scopolamine (SCO) for 4 weeks. We found that SCO-induced cognitive impairments, as assayed by the water maze and passive avoidance tests, were significantly reduced 1 week after SCO treatment and the impairments were maintained without any hippocampal neuronal loss. MBP-immunoreactive myelinated fibers were easily detected in the stratum radiatum and lacunosum-moleculare of the hippocampus proper (CA1-3 region) and in the molecular and polymorphic layers of the dentate gyrus. The distribution of MBP-immunoreactive myelinated fibers was not altered 1 week after SCO treatment. However, the density of MBP-immunoreactive myelinated fibers was significantly decreased 2 weeks after SCO treatment; thereafter, the density gradually, though not significantly, decreased with time. In addition, the changing pattern of MBP levels in the hippocampus following SCO treatment corresponded to immunohistochemical changes. In brief, this study shows that chronic systemic treatment with SCO induced significant degradation of MBP in the hippocampus without neuronal loss at least 2 weeks after SCO treatment, although cognitive impairments occurred 1 week after SCO treatment.

  13. Oxytocin via its receptor affects restraint stress-induced methamphetamine CPP reinstatement in mice: Involvement of the medial prefrontal cortex and dorsal hippocampus glutamatergic system.

    PubMed

    Han, Wen-Yan; Du, Ping; Fu, Shi-Yuan; Wang, Fang; Song, Ming; Wu, Chun-Fu; Yang, Jing-Yu

    2014-04-01

    Our previous study revealed that intracerebroventricular oxytocin (OT) markedly inhibited the restraint stress-priming conditioned place preference (CPP) reinstatement induced by methamphetamine (MAP) via the glutamatergic system. In this study, the effect of microinjection with OT into mesocorticolimbic regions, the medial prefrontal cortex (mPFC) and the dorsal hippocampus (DHC), on the restraint stress-priming CPP reinstatement were further studied. The results showed that a 15-min restraint stress significantly reinstated MAP-induced CPP, which was inhibited by the microinjection of OT (0.5 and 2.5μg/μl/mouse) into the mPFC. Atosiban (Ato), a selective inhibitor of OT receptor, could absolutely block the effect of OT (2.5μg/μl/mouse). The reinstatement was inhibited by microinjecting with OT (2.5 but not 0.5μg/μl/mouse) into the DHC, which could not be reversed by Ato. Western blotting results showed that the levels of GLT1, VGLUT2, NR2B, p-ERK1/2 and p-CREB expressions in the mPFC were increased and CaMKII was decreased markedly after the stress-priming MAP-induced CPP reinstatement test. OT blocked the changing levels of GLT1, VGLUT2, NR2B, p-CREB and CaMK II, which were reversed by Ato, but failed to affect the elevated expression of p-ERK1/2. In DHC, the levels of VGLUT2, p-ERK1/2 and CREB expressions were reduced during the stress-induced reinstatement, which could be reversed by OT and further abolished by Ato. The present results suggest that mPFC and DHC play differential roles in restraint stress-priming CPP reinstatement induced by MAP and OT via OT receptor affects the reinstatement in which the glutamatergic system is involved. Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.

  14. Astrocytic expression of HIV-1 viral protein R in the hippocampus causes chromatolysis, synaptic loss and memory impairment

    PubMed Central

    2014-01-01

    Background HIV-infected individuals are at an increased risk of developing neurological abnormalities. HIV induces neurotoxicity by host cellular factors and individual viral proteins. Some of these proteins including viral protein R (Vpr) promote immune activation and neuronal damage. Vpr is known to contribute to cell death of cultured rat hippocampal neurons and suppresses axonal growth. Behavioral studies are limited and suggest hyperactivity in the presence of Vpr. Thus Vpr may play a role in hippocampal loss of function. The purpose of this study is to determine the ability of HIV-1 Vpr production by astrocytes in the hippocampus to cause neurological deficits and memory impairments. Methods We tested the performance of rats in novel object and novel location tasks after hippocampal infusion with astrocytes expressing HIV-1 Vpr. Synaptic injury and morphological changes were measured by synaptophysin immunoreactivity and Nissl staining. Results Vpr-infused rats showed impaired novel location and novel object recognition compared with control rats expressing green fluorescent protein (GFP). This impairment was correlated with a significant decrease in synaptophysin immunoreactivity in the hippocampal CA3 region, suggesting synaptic injury in HIV-1 Vpr-treated animals. In addition, Nissl staining showed morphological changes indicative of neuronal chromatolysis in the Vpr group. The Vpr-induced neuronal damage and synaptic loss suggest that neuronal dysfunction caused the spatial and recognition memory deficits found in the Vpr-infused animals. Conclusions In this study, we demonstrate that HIV-1 Vpr produced by astrocytes in the hippocampus impairs hippocampal-dependent learning. The data suggest Vpr is a neurotoxin with the potential to cause learning impairment in HIV-1 infected individuals even under conditions of limited viral replication. PMID:24655810

  15. Nicotine versus 6-hydroxy-l-nicotine against chlorisondamine induced memory impairment and oxidative stress in the rat hippocampus.

    PubMed

    Hritcu, Lucian; Ionita, Radu; Motei, Diana Elena; Babii, Cornelia; Stefan, Marius; Mihasan, Marius

    2017-02-01

    6-Hydroxy-l-nicotine (6HLN), a nicotine derivative from nicotine degradation by Arthrobacter nicotinovorans pAO1 strain was found to improve behavioral deficits and to reverse oxidative stress in the rat hippocampus. Rats were given CHL (10mg/kg, i.p.) were used as an Alzheimer's disease-like model. The nicotine (0.3mg/kg) and 6HLN (0.3mg/kg) were administered alone or in combination in the CHL-treated rats. Memory-related behaviors were evaluated using Y-maze and radial arm-maze tests. The antioxidant enzymes activity and the levels of the biomarkers of oxidative stress were measured in the hippocampus. Statistical analyses were performed using two-way ANOVA and Tukey's post hoc test. F values for which p<0.05 were regarded as statistically significant. CHL-caused memory deficits and oxidative stress enhancing were observed. Both nicotine and 6HLN administration attenuated the cognitive deficits and recovered the antioxidant capacity in the rat hippocampus of the CHL rat model. Our results suggest that 6HLN versus nicotine confers anti-amnesic properties in the CHL-induced a rat model of memory impairment via reversing cholinergic function and decreasing brain oxidative stress, suggesting the use of this compound as an alternative agent in AD treatment. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  16. Cognition Enhancing and Neuromodulatory Propensity of Bacopa monniera Extract Against Scopolamine Induced Cognitive Impairments in Rat Hippocampus.

    PubMed

    Pandareesh, M D; Anand, T; Khanum, Farhath

    2016-05-01

    Cognition-enhancing activity of Bacopa monniera extract (BME) was evaluated against scopolamine-induced amnesic rats by novel object recognition test (NOR), elevated plus maze (EPM) and Morris water maze (MWM) tests. Scopolamine (2 mg/kg body wt, i.p.) was used to induce amnesia in rats. Piracetam (200 mg/kg body wt, i.p.) was used as positive control. BME at three different dosages (i.e., 10, 20 and 40 mg/kg body wt.) improved the impairment induced by scopolamine by increasing the discrimination index of NOR and by decreasing the transfer latency of EPM and escape latency of MWM tests. Our results further elucidate that BME administration has normalized the neurotransmitters (acetylcholine, glutamate, 5-hydroxytryptamine, dopamine, 3,4 dihydroxyphenylacetic acid, norepinephrine) levels that were altered by scopolamine administration in hippocampus of rat brain. BME administration also ameliorated scopolamine effect by down-regulating AChE and up-regulating BDNF, muscarinic M1 receptor and CREB expression in brain hippocampus confirms the potent neuroprotective role and these results are in corroboration with the earlier in vitro studies. BME administration showed significant protection against scopolamine-induced toxicity by restoring the levels of antioxidant and lipid peroxidation. These results indicate that, cognition-enhancing and neuromodulatory propensity of BME is through modulating the expression of AChE, BDNF, MUS-1, CREB and also by altering the levels of neurotransmitters in hippocampus of rat brain.

  17. PEGylated Carbon Nanotubes Impair Retrieval of Contextual Fear Memory and Alter Oxidative Stress Parameters in the Rat Hippocampus

    PubMed Central

    Dal Bosco, Lidiane; Weber, Gisele E. B.; Parfitt, Gustavo M.; Paese, Karina; Gonçalves, Carla O. F.; Serodre, Tiago M.; Furtado, Clascídia A.; Santos, Adelina P.; Monserrat, José M.; Barros, Daniela M.

    2015-01-01

    Carbon nanotubes (CNT) are promising materials for biomedical applications, especially in the field of neuroscience; therefore, it is essential to evaluate the neurotoxicity of these nanomaterials. The present work assessed the effects of single-walled CNT functionalized with polyethylene glycol (SWCNT-PEG) on the consolidation and retrieval of contextual fear memory in rats and on oxidative stress parameters in the hippocampus. SWCNT-PEG were dispersed in water at concentrations of 0.5, 1.0, and 2.1 mg/mL and infused into the rat hippocampus. The infusion was completed immediately after training and 30 min before testing of a contextual fear conditioning task, resulting in exposure times of 24 h and 30 min, respectively. The results showed that a short exposure to SWCNT-PEG impaired fear memory retrieval and caused lipid peroxidation in the hippocampus. This response was transient and overcome by the mobilization of antioxidant defenses at 24 h. These effects occurred at low and intermediate but not high concentration of SWCNT-PEG, suggesting that the observed biological response may be related to the concentration-dependent increase in particle size in SWCNT-PEG dispersions. PMID:25738149

  18. Early enriched physical environment reverses impairments of the hippocampus, but not medial prefrontal cortex, of adolescent socially-isolated Mice.

    PubMed

    Cao, Min; Pu, Tinglin; Wang, Linmei; Marshall, Charles; He, Hongliang; Hu, Gang; Xiao, Ming

    2017-04-12

    Early social isolation (SI) produces a variety of emotional, behavioral and cognitive abnormalities. Conversely, environmental enrichment (EE), a complicated social and physical construct, offers beneficial effects on brain plasticity and development. However, whether or not exclusive physical EE is sufficient to reverse the adverse consequences of adolescent SI remains unclear. Here we reported that 1 month-old solitary mice housed in the EE for 8 weeks corrected spatial cognitive dysfunction, but did not ameliorate social interaction deficits and increased anxiety-like behavior. Pathological analyses revealed that the enriched environment decreased cellular apoptosis, synaptic protein loss, myelination defect and microglial activation in the hippocampus, but not medial prefrontal cortex (mPFC) of mice housed singly. Moreover, increased nuclear factor-kappaB and interleukin-1β levels, and downregulation of brain-derived neurotrophic factor signaling pathway were normalized in the hippocampus rather than mPFC of these animals. Our results revealed a brain region-specific effectiveness of physical EE in remediating brain impairment of adolescent SI mice, with a complete reversal of hippocampus-dependent cognitive dysfunctions, but without mitigation of mPFC associated anxiety and social interaction defects. This finding emphasizes the irreplaceable role of social life for the early brain development.

  19. Experience Modulates the Effects of Histone Deacetylase Inhibitors on Gene and Protein Expression in the Hippocampus: Impaired Plasticity in Aging

    PubMed Central

    Sewal, Angila S.; Patzke, Holger; Perez, Evelyn J.; Park, Pul; Lehrmann, Elin; Zhang, Yongqing; Becker, Kevin G.; Fletcher, Bonnie R.; Long, Jeffrey M.

    2015-01-01

    The therapeutic potential of histone deacetylase inhibitor (HDACi) treatment has attracted considerable attention in the emerging area of cognitive neuroepigenetics. The possibility that ongoing cognitive experience importantly regulates the cell biological effects of HDACi administration, however, has not been systematically examined. In an initial experiment addressing this issue, we tested whether water maze training influences the gene expression response to acute systemic HDACi administration in the young adult rat hippocampus. Training powerfully modulated the response to HDACi treatment, increasing the total number of genes regulated to nearly 3000, including many not typically linked to neural plasticity, compared with <300 following HDACi administration alone. Although water maze training itself also regulated nearly 1800 genes, the specific mRNAs, gene networks, and biological pathways involved were largely distinct when the same experience was provided together with HDACi administration. Next, we tested whether the synaptic protein response to HDACi treatment is similarly dependent on recent cognitive experience, and whether this plasticity is altered in aged rats with memory impairment. Whereas synaptic protein labeling in the young hippocampus was selectively increased when HDACi administration was provided in conjunction with water maze training, combined treatment had no effect on synaptic proteins in the aged hippocampus. Our findings indicate that ongoing experience potently regulates the molecular consequences of HDACi treatment and that the interaction of recent cognitive experience with histone acetylation dynamics is disrupted in the aged hippocampus. SIGNIFICANCE STATEMENT The possibility that interventions targeting epigenetic regulation could be effective in treating a range of neurodegenerative disorders has attracted considerable interest. Here we demonstrate in the rat hippocampus that ongoing experience powerfully modifies the molecular

  20. The Parkinson's Disease-Associated Mutation LRRK2-G2019S Impairs Synaptic Plasticity in Mouse Hippocampus

    PubMed Central

    Sweet, Eric S.; Saunier-Rebori, Bernadette

    2015-01-01

    Parkinson's disease (PD) is a major movement disorder characterized by the loss of dopamine neurons and formation of Lewy bodies. Clinical and pathological evidence indicates that multiple brain regions are affected in PD in a spatiotemporal manner and are associated with a variety of motor and nonmotor symptoms, including disturbances in mood, executive function, and memory. The common PD-associated gene for leucine-rich repeat kinase, leucine-rich repeat kinase 2 (LRRK2), is highly expressed in brain regions that are involved with nonmotor functions, including the neocortex and hippocampus, but whether mutant LRRK2 contributes to neuronal dysfunction in these regions is unknown. Here, we use bacterial artificial chromosome transgenic mouse models of LRRK2 to explore potential nonmotor mechanisms of PD. Through electrophysiological analysis of the Schaffer collateral–CA1 synapse in dorsal hippocampus, we find that overexpression of LRRK2-G2019S increases basal synaptic efficiency through a postsynaptic mechanism, and disrupts long-term depression. Furthermore, these effects of the G2019S mutation are age dependent and can be normalized by acute inhibition of LRRK2 kinase activity. In contrast, overexpression of wild-type LRRK2 has no effect under the same conditions, suggesting a specific phenotype for the G2019S mutation. These results identify a pathogenic function of LRRK2 in the hippocampus that may contribute to nonmotor symptoms of PD. SIGNIFICANCE STATEMENT Parkinson's disease (PD) is among the most common neurological diseases and is best known for its adverse effects on brain regions that control motor function, resulting in tremor, rigidity, and gait abnormalities. Less well appreciated are the psychiatric symptoms experienced by many PD patients, including depression and memory loss, which do not respond well to currently available treatments for PD. Here, we describe functional effects of a common PD-linked mutation of leucine-rich repeat kinase 2 in

  1. Modifications in resting state functional anticorrelation between default mode network and dorsal attention network: comparison among young adults, healthy elders and mild cognitive impairment patients.

    PubMed

    Esposito, Roberto; Cieri, Filippo; Chiacchiaretta, Piero; Cera, Nicoletta; Lauriola, Mariella; Di Giannantonio, Massimo; Tartaro, Armando; Ferretti, Antonio

    2017-02-07

    Resting state brain activity incorporates different components, including the Default Mode Network and the Dorsal Attention Network, also known as task-negative network and task-positive network respectively. These two networks typically show an anticorrelated activity during both spontaneous oscillations and task execution. However modifications of this anticorrelated activity pattern with age and pathology are still unclear. The present study aimed to investigate differences in resting state Default Mode Network-Dorsal Attention Network functional anticorrelation among young adults, healthy elders and Mild Cognitive Impairment patients. We retrospectively enrolled in this study 27 healthy young adults (age range: 25-35 y.o.; mean age: 28,5), 26 healthy elders (age range: 61-72 y.o.; mean age: 65,1) and 17 MCI patients (age range 64-87 y.o.; mean age: 73,6). Mild Cognitive Impairment patients were selected following Petersen criteria. All participants underwent neuropsychological evaluation and resting state functional Magnetic Resonance Imaging. Spontaneous anticorrelated activity between Default Mode Network and Dorsal Attention Network was observed in each group. This anticorrelation was significantly decreased with age in most Default Mode Network-Dorsal Attention Network connections (p < 0.001, False Discovery Rate corrected). Moreover, the anticorrelation between the posterior cingulate cortex node of the Default Mode Network and the right inferior parietal sulcus node of the Dorsal Attention Network was significantly decreased when comparing Mild Cognitive Impairment with normal elders (p < 0.001, False Discovery Rate corrected). The functional connectivity changes in patients were not related to significant differences in grey matter content. Our results suggest that a reduced anticorrelated activity between Default Mode Network and Dorsal Attention Network is part of the normal aging process and that Mild Cognitive Impairment status is associated with

  2. Persistent impairments in hippocampal, dorsal striatal, and prefrontal cortical function following repeated photoperiod shifts in rats.

    PubMed

    Zelinski, Erin L; Tyndall, Amanda V; Hong, Nancy S; McDonald, Robert J

    2013-01-01

    Cognitive impairments are observed when learned associations are being acquired or retrieved during a period of circadian disruption. However, the extent of the functional impacts on previously acquired associations following circadian rhythm re-entrainment is unknown. The impacts of repeated photoperiod shifts on learning and memory in male and female rats were examined. For these experiments, rats were trained on a spatial version of the Morris water task (MWT) and a visual discrimination task designed for the 8-arm radial maze. Following asymptotic performance on these tasks, rats experienced a repeating photoperiod shift procedure and were then re-entrained. Following circadian re-entrainment, retention of pre-photoperiod-shift-acquired associations was tested. In addition, an extra-dimensional set shift was performed using the 8-arm radial maze. Impaired retention of the MWT platform location was observed in photoperiod-shifted subjects relative to subjects with stable, unmanipulated photoperiods. Repeated photoperiod shifts negatively impacted retention in males and females compared with subjects with stable photoperiods. Retention and the ability to detect extra-dimensional shifts on the visual discrimination task were also impaired, though not consistently by sex or photoperiod condition. Running wheel availability was also included in the analyses to determine whether exercise influenced the effects of photoperiod shifting. The absence of a running wheel produced significant declines in memory retention on both MWT and the visual discrimination task, but only for male rats. The observed impairments indicate that multiple neural systems supporting different learning and memory functions are susceptible to circadian disruption, even if the association is acquired prior to rhythm fragmentation and tested following rhythm re-entrainment.

  3. Long-Term Memory for Place Learning Is Facilitated by Expression of cAMP Response Element-Binding Protein in the Dorsal Hippocampus

    ERIC Educational Resources Information Center

    Brightwell, Jennifer J.; Smith, Clayton A.; Neve, Rachael L.; Colombo, Paul J.

    2007-01-01

    Extensive research has shown that the hippocampus is necessary for consolidation of long-term spatial memory in rodents. We reported previously that rats using a place strategy to solve a cross maze task showed sustained phosphorylation of hippocampus cyclic AMP response element-binding protein (CREB), a transcription factor implicated in…

  4. Long-Term Memory for Place Learning Is Facilitated by Expression of cAMP Response Element-Binding Protein in the Dorsal Hippocampus

    ERIC Educational Resources Information Center

    Brightwell, Jennifer J.; Smith, Clayton A.; Neve, Rachael L.; Colombo, Paul J.

    2007-01-01

    Extensive research has shown that the hippocampus is necessary for consolidation of long-term spatial memory in rodents. We reported previously that rats using a place strategy to solve a cross maze task showed sustained phosphorylation of hippocampus cyclic AMP response element-binding protein (CREB), a transcription factor implicated in…

  5. CHRONIC DEVELOPMENTAL LEAD EXPOSURE REDUCES NEUROGENESIS IN ADULT RAT HIPPOCAMPUS BUT DOES NOT IMPAIR SPATIAL LEARNING.

    EPA Science Inventory

    It has long been heralded that the mature brain does not generate new neurons, it only loses them as a function of injury, disease and age. An exciting recent finding in neuroscience has been that the dentate granule cell layer of the hippocampus has the distinctive property of ...

  6. CHRONIC DEVELOPMENTAL LEAD EXPOSURE REDUCES NEUROGENESIS IN ADULT RAT HIPPOCAMPUS BUT DOES NOT IMPAIR SPATIAL LEARNING.

    EPA Science Inventory

    It has long been heralded that the mature brain does not generate new neurons, it only loses them as a function of injury, disease and age. An exciting recent finding in neuroscience has been that the dentate granule cell layer of the hippocampus has the distinctive property of ...

  7. Disruption of the Perineuronal Net in the Hippocampus or Medial Prefrontal Cortex Impairs Fear Conditioning

    ERIC Educational Resources Information Center

    Hylin, Michael J.; Orsi, Sara A.; Moore, Anthony N.; Dash, Pramod K.

    2013-01-01

    The perineuronal net (PNN) surrounds neurons in the central nervous system and is thought to regulate developmental plasticity. A few studies have shown an involvement of the PNN in hippocampal plasticity and memory storage in adult animals. In addition to the hippocampus, plasticity in the medial prefrontal cortex (mPFC) has been demonstrated to…

  8. Disruption of the Perineuronal Net in the Hippocampus or Medial Prefrontal Cortex Impairs Fear Conditioning

    ERIC Educational Resources Information Center

    Hylin, Michael J.; Orsi, Sara A.; Moore, Anthony N.; Dash, Pramod K.

    2013-01-01

    The perineuronal net (PNN) surrounds neurons in the central nervous system and is thought to regulate developmental plasticity. A few studies have shown an involvement of the PNN in hippocampal plasticity and memory storage in adult animals. In addition to the hippocampus, plasticity in the medial prefrontal cortex (mPFC) has been demonstrated to…

  9. Trace and contextual fear conditioning are impaired following unilateral microinjection of muscimol in the ventral hippocampus or amygdala, but not the medial prefrontal cortex

    PubMed Central

    Gilmartin, Marieke R.; Kwapis, Janine L.; Helmstetter, Fred J.

    2012-01-01

    Trace fear conditioning, in which a brief empty “trace interval” occurs between presentation of the CS and UCS, differs from standard delay conditioning in that contributions from both the hippocampus and prelimbic medial prefrontal cortex (PL mPFC) are required to form a normal long term memory. Little is currently known about how the PL interacts with various temporal lobe structures to support learning across this temporal gap between stimuli. We temporarily inactivated PL along with either ventral hippocampus or amygdala in a disconnection design to determine if these structures functionally interact to acquire trace fear conditioning. Disconnection (contralateral injections) of the PL with either the ventral hippocampus or amygdala impaired trace fear conditioning; however, ipsilateral control rats were also impaired. Follow-up experiments examined the effects of unilateral inactivation of the PL, ventral hippocampus, or amygdala during conditioning. The results of this study demonstrate that unilateral inactivation of the ventral hippocampus or amygdala impairs memory, while bilateral inactivation of the PL is required to produce a deficit. Memory deficits after unilateral inactivation of the ventral hippocampus or amygdala prevent us from determining whether the mPFC functionally interacts with the medial temporal lobe using a disconnection approach. Nonetheless, our findings suggest that the trace fear network is more integrated than previously thought. PMID:22469748

  10. Diagnostic differentiation of mild cognitive impairment due to Alzheimer's disease using a hippocampus-dependent test of spatial memory.

    PubMed

    Moodley, Kuven; Minati, Ludovico; Contarino, Valeria; Prioni, Sara; Wood, Ruth; Cooper, Rebecca; D'Incerti, Ludovico; Tagliavini, Fabrizio; Chan, Dennis

    2015-08-01

    The hippocampus is one of the earliest brain regions affected in Alzheimer's disease (AD) and tests of hippocampal function have the potential to detect AD in its earliest stages. Given that the hippocampus is critically involved in allocentric spatial memory, this study applied a short test of spatial memory, the 4 Mountains Test (4MT), to determine whether test performance can differentiate mild cognitive impairment (MCI) patients with and without CSF biomarker evidence of underlying AD and whether the test can distinguish patients with MCI and mild AD dementia when applied in different cultural settings. Healthy controls (HC), patients with MCI, and mild AD dementia were recruited from study sites in UK and Italy. Study numbers were: HC (UK 20, Italy 10), MCI (UK 21, Italy 14), and AD (UK 11, Italy 9). Nineteen UK MCI patients were grouped into CSF biomarker-positive (MCI+, n = 10) and biomarker-negative (MCI-, n = 9) subgroups. Behavioral data were correlated with hippocampal volume and cortical thickness of the precuneus and posterior cingulate gyrus. Spatial memory was impaired in both UK and Italy MCI and AD patients. Test performance additionally differentiated between MCI+ and MCI- subgroups (P = 0.001). A 4MT score of ≤8/15 was associated with 100% sensitivity and 90% specificity for detection of early AD (MCI+ and mild AD dementia) in the UK population, and with 100% sensitivity and 50% specificity for detection of MCI and AD in the Italy sample. 4MT performance correlated with hippocampal volume in the UK population and cortical thickness of the precuneus in both study populations. In conclusion, performance on a hippocampus-sensitive test of spatial memory differentiates MCI due to AD with high diagnostic sensitivity and specificity. The observation that similar diagnostic sensitivity was obtained in two separate study populations, allied to the scalability and usability of the test in community memory clinics, supports future application of the 4MT

  11. A1 adenosine receptor-mediated GIRK channels contribute to the resting conductance of CA1 neurons in the dorsal hippocampus

    PubMed Central

    Kim, Chung Sub

    2015-01-01

    The dorsal and ventral hippocampi are functionally and anatomically distinct. Recently, we reported that dorsal Cornu Ammonis area 1 (CA1) neurons have a more hyperpolarized resting membrane potential and a lower input resistance and fire fewer action potentials for a given current injection than ventral CA1 neurons. Differences in the hyperpolarization-activated cyclic nucleotide-gated cation conductance between dorsal and ventral neurons have been reported, but these differences cannot fully account for the different resting properties of these neurons. Here, we show that coupling of A1 adenosine receptors (A1ARs) to G-protein-coupled inwardly rectifying potassium (GIRK) conductance contributes to the intrinsic membrane properties of dorsal CA1 neurons but not ventral CA1 neurons. The block of GIRKs with either barium or the more specific blocker Tertiapin-Q revealed that there is more resting GIRK conductance in dorsal CA1 neurons compared with ventral CA1 neurons. We found that the higher resting GIRK conductance in dorsal CA1 neurons was mediated by tonic A1AR activation. These results demonstrate that the different resting membrane properties between dorsal and ventral CA1 neurons are due, in part, to higher A1AR-mediated GIRK activity in dorsal CA1 neurons. PMID:25652929

  12. Inhibition of GABA A receptor improved special memory impairment in the local model of demyelination in rat hippocampus.

    PubMed

    Mousavi Majd, Alireza; Ebrahim Tabar, Forough; Afghani, Arghavan; Ashrafpour, Sahand; Dehghan, Samaneh; Gol, Mohammad; Ashrafpour, Manouchehr; Pourabdolhossein, Fereshteh

    2018-01-15

    Cognitive impairment and memory deficit are common features in multiple Sclerosis patients. The mechanism of memory impairment in MS is unknown, but neuroimaging studies suggest that hippocampal demyelination is involved. Here, we investigate the role of GABA A receptor on spatial memory in the local model of hippocampal demyelination. Demyelination was induced in male Wistar rats by bilaterally injection of lysophosphatidylcholine (LPC) 1% into the CA1 region of the hippocampus. The treatment groups were received daily intraventricular injection of bicuculline (0.025, 0.05μg/2μl/animal) or muscimol (0.1, 0.2μg/2μl/animal) 5days after LPC injection. Morris Water Maze was used to evaluate learning and memory in rats. We used Luxol fast blue staining and qPCR to assess demyelination extention and MBP expression level respectively. Immunohistochemistry (IHC) for CD45 and H&E staining were performed to assess inflammatory cells infiltration. Behavioral study revealed that LPC injection in the hippocampus impaired learning and memory function. Animals treated with both doses of bicuculline improved spatial learning and memory function; however, muscimol treatment had no effect. Histological and MBP expression studies confirmed that demylination in LPC group was maximal. Bicuculline treatment significantly reduced demyelination extension and increased the level of MBP expression. H&E and IHC results showed that bicuculline reduced inflammatory cell infiltration in the lesion site. Bicuculline improved learning and memory and decreased demyelination extention in the LPC-induced hippocampal demyelination model. We conclude that disruption of GABAergic homeostasis in hippocampal demyelination context may be involved in memory impairment with the implications for both pathophysiology and therapy. Copyright © 2017. Published by Elsevier B.V.

  13. The role of the direct perforant path input to the CA1 subregion of the dorsal hippocampus in memory retention and retrieval.

    PubMed

    Vago, David R; Bevan, Adam; Kesner, Raymond P

    2007-01-01

    Subregional analyses of the hippocampus have suggested a selective role for the CA1 subregion in intermediate/long-term spatial memory and consolidation, but not short-term acquisition or encoding processes. It remains unclear how the direct cortical projection to CA1 via the perforant path (pp) contributes to these CA1-dependent processes. It has been suggested that dopamine selectively modulates the pp projection to CA1 while having little to no effect on the Schaffer collateral (SC) projection to CA1. This series of behavioral and electrophysiological experiments takes advantage of this pharmacological dissociation to demonstrate that the direct pp inputs to CA1 are critical in CA1-dependent intermediate-term retention and retrieval function. Here we demonstrate that local infusion of the nonselective dopamine agonist, apomorphine (10, 15 microg), into the CA1 subregion of awake animals produces impairments in between-day retention and retrieval, sparing within-day encoding of a modified Hebb-Williams maze and contextual conditioning of fear. In contrast, apomorphine produces no deficits when infused into the CA3 subregion. To complement the behavioral analyses, electrophysiological data was collected. In anesthetized animals, local infusion of the same doses of apomorphine significantly modifies evoked responses in the distal dendrites of CA1 following angular bundle stimulation, but produces no significant effects in the more proximal dendritic layer following stimulation of the SC. These results support a modulatory role for dopamine in the EC-CA1, but not CA3-CA1 circuitry, and suggest the possibility of a more fundamental role for EC-CA1 synaptic transmission in terms of intermediate-term, but not short-term spatial memory.

  14. Early postnatal nicotine exposure causes hippocampus-dependent memory impairments in adolescent mice: Association with altered nicotinic cholinergic modulation of LTP, but not impaired LTP.

    PubMed

    Nakauchi, Sakura; Malvaez, Melissa; Su, Hailing; Kleeman, Elise; Dang, Richard; Wood, Marcelo A; Sumikawa, Katumi

    2015-02-01

    Fetal nicotine exposure from smoking during pregnancy causes long-lasting cognitive impairments in offspring, yet little is known about the mechanisms that underlie this effect. Here we demonstrate that early postnatal exposure of mouse pups to nicotine via maternal milk impairs long-term, but not short-term, hippocampus-dependent memory during adolescence. At the Schaffer collateral (SC) pathway, the most widely studied synapses for a cellular correlate of hippocampus-dependent memory, the induction of N-methyl-D-aspartate receptor-dependent transient long-term potentiation (LTP) and protein synthesis-dependent long-lasting LTP are not diminished by nicotine exposure, but rather unexpectedly the threshold for LTP induction becomes lower after nicotine treatment. Using voltage sensitive dye to visualize hippocampal activity, we found that early postnatal nicotine exposure also results in enhanced CA1 depolarization and hyperpolarization after SC stimulation. Furthermore, we show that postnatal nicotine exposure induces pervasive changes to the nicotinic modulation of CA1 activity: activation of nicotinic receptors no longer increases CA1 network depolarization, acute nicotine inhibits rather than facilitates the induction of LTP at the SC pathway by recruiting an additional nicotinic receptor subtype, and acute nicotine no longer blocks LTP induction at the temporoammonic pathway. These findings reflect the pervasive impact of nicotine exposure during hippocampal development, and demonstrate an association of hippocampal memory impairments with altered nicotinic cholinergic modulation of LTP, but not impaired LTP. The implication of our results is that nicotinic cholinergic-dependent plasticity is required for long-term memory formation and that postnatal nicotine exposure disrupts this form of plasticity.

  15. Chronic restraint stress promotes learning and memory impairment due to enhanced neuronal endoplasmic reticulum stress in the frontal cortex and hippocampus in male mice.

    PubMed

    Huang, Rong-Rong; Hu, Wen; Yin, Yan-Yan; Wang, Yu-Chan; Li, Wei-Ping; Li, Wei-Zu

    2015-02-01

    Chronic stress has been implicated in many types of neurodegenerative diseases, such as Alzheimer's disease (AD). In our previous study, we demonstrated that chronic restraint stress (CRS) induced reactive oxygen species (ROS) overproduction and oxidative damage in the frontal cortex and hippocampus in mice. In the present study, we investigated the effects of CRS (over a period of 8 weeks) on learning and memory impairment and endoplasmic reticulum (ER) stress in the frontal cortex and hippocampus in male mice. The Morris water maze was used to investigate the effects of CRS on learning and memory impairment. Immunohistochemistry and immunoblot analysis were also used to determine the expression levels of protein kinase C α (PKCα), 78 kDa glucose-regulated protein (GRP78), C/EBP-homologous protein (CHOP) and mesencephalic astrocyte-derived neurotrophic factor (MANF). The results revealed that CRS significantly accelerated learning and memory impairment, and induced neuronal damage in the frontal cortex and hippocampus CA1 region. Moreover, CRS significantly increased the expression of PKCα, CHOP and MANF, and decreased that of GRP78 in the frontal cortex and hippocampus. Our data suggest that exposure to CRS (for 8 weeks) significantly accelerates learning and memory impairment, and the mechanisms involved may be related to ER stress in the frontal cortex and hippocampus.

  16. Synaptophysin and the dopaminergic system in hippocampus are involved in the protective effect of rutin against trimethyltin-induced learning and memory impairment.

    PubMed

    Zhang, Lei; Zhao, Qi; Chen, Chun-Hai; Qin, Qi-Zhong; Zhou, Zhou; Yu, Zheng-Ping

    2014-09-01

    This study aimed to investigate the protective effect of rutin against trimethyltin-induced spatial learning and memory impairment in mice. This study focused on the role of synaptophysin, growth-associated protein 43 and the action of the dopaminergic system in mechanisms associated with rutin protection and trimethyltin-induced spatial learning and memory impairment. Cognitive learning and memory was measured by Morris Water Maze. The expression of synaptophysin and growth-associated protein 43 in hippocampus was analyzed by western blot. The concentrations of dopamine, homovanillic acid, and dihyroxyphenylacetic acid in hippocampus were detected using reversed phase high-performance liquid chromatography with electrochemical detection. Trimethyltin-induced spatial learning impairment showed a dose-dependent mode. Synaptophysin but not growth-associated protein 43 was decreased in the hippocampus after trimethyltin administration. The concentration of dopamine decreased, while homovanillic acid increased in the hippocampus after trimethyltin administration. Mice pretreated with 20 mg/kg of rutin for 7 consecutive days exhibited improved water maze performance. Moreover, rutin pretreatment reversed the decrease of synaptophysin expression and dopamine alteration. These results suggest that rutin may protect against spatial memory impairment induced by trimethyltin. Synaptophysin and the dopaminergic system may be involved in trimethyltin-induced neuronal damage in hippocampus.

  17. Ginsenoside Rg1 Prevents Cognitive Impairment and Hippocampus Senescence in a Rat Model of D-Galactose-Induced Aging

    PubMed Central

    Zeng, Jin; Xu, Chunyan; Liu, Jun; Zhang, Mengsi; Li, Chengpeng; Chen, Jie; Li, Tinyu; Wang, Yaping

    2014-01-01

    Neurogenesis continues throughout the lifetime in the hippocampus, while the rate declines with brain aging. It has been hypothesized that reduced neurogenesis may contribute to age-related cognitive impairment. Ginsenoside Rg1 is an active ingredient of Panax ginseng in traditional Chinese medicine, which exerts anti-oxidative and anti-aging effects. This study explores the neuroprotective effect of ginsenoside Rg1 on the hippocampus of the D-gal (D-galactose) induced aging rat model. Sub-acute aging was induced in male SD rats by subcutaneous injection of D-gal (120 mg/kg·d) for 42 days, and the rats were treated with ginsenoside Rg1 (20 mg/kg·d, intraperitoneally) or normal saline for 28 days after 14 days of D-gal injection. In another group, normal male SD rats were treated with ginsenoside Rg1 alone (20 mg/kg·d, intraperitoneally) for 28 days. It showed that administration of ginsenoside Rg1 significantly attenuated all the D-gal-induced changes in the hippocampus, including cognitive capacity, senescence-related markers and hippocampal neurogenesis, compared with the D-gal-treated rats. Further investigation showed that ginsenoside Rg1 protected NSCs/NPCs (neural stem cells/progenitor cells) shown by increased level of SOX-2 expression; reduced astrocytes activation shown by decrease level of Aeg-1 expression; increased the hippocampal cell proliferation; enhanced the activity of the antioxidant enzymes GSH-Px (glutathione peroxidase) and SOD (Superoxide Dismutase); decreased the levels of IL-1β, IL-6 and TNF-α, which are the proinflammatory cytokines; increased the telomere lengths and telomerase activity; and down-regulated the mRNA expression of cellular senescence associated genes p53, p21Cip1/Waf1 and p19Arf in the hippocampus of aged rats. Our data provides evidence that ginsenoside Rg1 can improve cognitive ability, protect NSCs/NPCs and promote neurogenesis by enhancing the antioxidant and anti-inflammatory capacity in the hippocampus. PMID

  18. Ginsenoside Rg1 prevents cognitive impairment and hippocampus senescence in a rat model of D-galactose-induced aging.

    PubMed

    Zhu, Jiahong; Mu, Xinyi; Zeng, Jin; Xu, Chunyan; Liu, Jun; Zhang, Mengsi; Li, Chengpeng; Chen, Jie; Li, Tinyu; Wang, Yaping

    2014-01-01

    Neurogenesis continues throughout the lifetime in the hippocampus, while the rate declines with brain aging. It has been hypothesized that reduced neurogenesis may contribute to age-related cognitive impairment. Ginsenoside Rg1 is an active ingredient of Panax ginseng in traditional Chinese medicine, which exerts anti-oxidative and anti-aging effects. This study explores the neuroprotective effect of ginsenoside Rg1 on the hippocampus of the D-gal (D-galactose) induced aging rat model. Sub-acute aging was induced in male SD rats by subcutaneous injection of D-gal (120 mg/kg·d) for 42 days, and the rats were treated with ginsenoside Rg1 (20 mg/kg·d, intraperitoneally) or normal saline for 28 days after 14 days of D-gal injection. In another group, normal male SD rats were treated with ginsenoside Rg1 alone (20 mg/kg·d, intraperitoneally) for 28 days. It showed that administration of ginsenoside Rg1 significantly attenuated all the D-gal-induced changes in the hippocampus, including cognitive capacity, senescence-related markers and hippocampal neurogenesis, compared with the D-gal-treated rats. Further investigation showed that ginsenoside Rg1 protected NSCs/NPCs (neural stem cells/progenitor cells) shown by increased level of SOX-2 expression; reduced astrocytes activation shown by decrease level of Aeg-1 expression; increased the hippocampal cell proliferation; enhanced the activity of the antioxidant enzymes GSH-Px (glutathione peroxidase) and SOD (Superoxide Dismutase); decreased the levels of IL-1β, IL-6 and TNF-α, which are the proinflammatory cytokines; increased the telomere lengths and telomerase activity; and down-regulated the mRNA expression of cellular senescence associated genes p53, p21Cip1/Waf1 and p19Arf in the hippocampus of aged rats. Our data provides evidence that ginsenoside Rg1 can improve cognitive ability, protect NSCs/NPCs and promote neurogenesis by enhancing the antioxidant and anti-inflammatory capacity in the hippocampus.

  19. Short-term sleep deprivation impairs spatial working memory and modulates expression levels of ionotropic glutamate receptor subunits in hippocampus.

    PubMed

    Xie, Meilan; Yan, Jie; He, Chao; Yang, Li; Tan, Gang; Li, Chao; Hu, Zhian; Wang, Jiali

    2015-06-01

    Hippocampus-dependent learning memory is sensitive to sleep deprivation (SD). Although the ionotropic glutamate receptors play a vital role in synaptic plasticity and learning and memory, however, whether the expression of these receptor subunits is modulated by sleep loss remains unclear. In the present study, western blotting was performed by probing with specific antibodies against the ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits GluA1, GluA2, GluA3, and against the N-methyl-d-aspartate (NMDA) glutamate receptor subunits GluN1, GluN2A, GluN2B. In hippocampus, down regulation of surface GluA1 and GluN2A surface expression were observed in both SD groups. However, surface expression level of GluA2, GluA3, GluN1 and GluN2B was significantly up-regulated in 8h-SD rats when compared to the 4h-SD rats. In parallel with the complex changes in AMPA and NMDA receptor subunit expressions, we found the 8h-SD impaired rat spatial working memory in 30-s-delay T-maze task, whereas no impairment of spatial learning was observed in 4h-SD rats. These results indicate that sleep loss alters the relative expression levels of the AMPA and NMDA receptors, thus affects the synaptic strength and capacity for plasticity and partially contributes to spatial memory impairment.

  20. Neuropathy-associated Nav1.7 variant I228M impairs integrity of dorsal root ganglion neuron axons.

    PubMed

    Persson, Anna-Karin; Liu, Shujun; Faber, Catharina G; Merkies, Ingemar S J; Black, Joel A; Waxman, Stephen G

    2013-01-01

    Small-fiber neuropathy (SFN) is characterized by injury to small-diameter peripheral nerve axons and intraepidermal nerve fibers (IENF). Although mechanisms underlying loss of IENF in SFN are poorly understood, available data suggest that it results from axonal degeneration and reduced regenerative capacity. Gain-of-function variants in sodium channel Na(V)1.7 that increase firing frequency and spontaneous firing of dorsal root ganglion (DRG) neurons have recently been identified in ∼30% of patients with idiopathic SFN. In the present study, to determine whether these channel variants can impair axonal integrity, we developed an in vitro assay of DRG neurite length, and examined the effect of 3 SFN-associated variant Na(V)1.7 channels, I228M, M932L/V991L (ML/VL), and I720K, on DRG neurites in vitro. At 3 days after culturing, DRG neurons transfected with I228M channels exhibited ∼20% reduced neurite length compared to wild-type channels; DRG neurons transfected with ML/VL and I720K variants displayed a trend toward reduced neurite length. I228M-induced reduction in neurite length was ameliorated by the use-dependent sodium channel blocker carbamazepine and by a blocker of reverse Na-Ca exchange. These in vitro observations provide evidence supporting a contribution of the I228M variant Na(V)1.7 channel to impaired regeneration and/or degeneration of sensory axons in idiopathic SFN, and suggest that enhanced sodium channel activity and reverse Na-Ca exchange can contribute to a decrease in length of peripheral sensory axons.

  1. Multi-modal MRI investigation of volumetric and microstructural changes in the hippocampus and its subfields in mild cognitive impairment, Alzheimer's disease, and dementia with Lewy bodies.

    PubMed

    Mak, Elijah; Gabel, Silvy; Su, Li; Williams, Guy B; Arnold, Robert; Passamonti, Luca; Vazquez Rodríguez, Patricia; Surendranathan, Ajenthan; Bevan-Jones, W Richard; Rowe, James B; O'Brien, John T

    2017-04-01

    Volumetric atrophy and microstructural alterations in diffusion tensor imaging (DTI) measures of the hippocampus have been reported in people with Alzheimer's disease (AD) and mild cognitive impairment (MCI). However, no study to date has jointly investigated concomitant microstructural and volumetric changes of the hippocampus in dementia with Lewy bodies (DLB). A total of 84 subjects (23 MCI, 17 DLB, 14 AD, and 30 healthy controls) were recruited for a multi-modal imaging (3T MRI and DTI) study that included neuropsychological evaluation. Freesurfer was used to segment the total hippocampus and delineate its subfields. The hippocampal segmentations were co-registered to the mean diffusivity (MD) and fractional anisotropy (FA) maps obtained from the DTI images. Both AD and MCI groups showed significantly smaller hippocampal volumes compared to DLB and controls, predominantly in the CA1 and subiculum subfields. Compared to controls, hippocampal MD was elevated in AD, but not in MCI. DLB was characterized by both volumetric and microstructural preservation of the hippocampus. In MCI, higher hippocampal MD was associated with greater atrophy of the hippocampus and CA1 region. Hippocampal volume was a stronger predictor of memory scores compared to MD within the MCI group. Through a multi-modal integration, we report novel evidence that the hippocampus in DLB is characterized by both macrostructural and microstructural preservation. Contrary to recent suggestions, our findings do not support the view that DTI measurements of the hippocampus are superior to volumetric changes in characterizing group differences, particularly between MCI and controls.

  2. Pre-training administration of tianeptine, but not propranolol, protects hippocampus-dependent memory from being impaired by predator stress.

    PubMed

    Campbell, Adam M; Park, Collin R; Zoladz, Phillip R; Muñoz, Carmen; Fleshner, Monika; Diamond, David M

    2008-02-01

    Extensive research has shown that the antidepressant tianeptine blocks the adverse effects of chronic stress on hippocampal functioning. The current series of experiments extended this area of investigation by examining the influence of tianeptine on acute stress-induced impairments of spatial (hippocampus-dependent) memory. Tianeptine (10 mg/kg, ip) administered to adult male rats before, but not after, water maze training blocked the amnestic effects of predator stress (occurring between training and retrieval) on memory. The protective effects of tianeptine on memory occurred in rats which had extensive pre-stress training, as well as in rats which had only a single day of training. Tianeptine blocked stress effects on memory without altering the stress-induced increase in corticosterone levels. Propranolol, a beta-adrenergic receptor antagonist (5 and 10 mg/kg, ip), in contrast, did not block stress-induced amnesia. These findings indicate that treatment with tianeptine, unlike propanolol, provides an effective means with which to block the adverse effects of stress on cognitive functions of the hippocampus.

  3. Altered amygdala and hippocampus effective connectivity in mild cognitive impairment patients with depression: a resting-state functional MR imaging study with granger causality analysis.

    PubMed

    Zheng, Li Juan; Yang, Gui Fen; Zhang, Xin Yuan; Wang, Yun Fei; Liu, Ya; Zheng, Gang; Lu, Guang Ming; Zhang, Long Jiang; Han, Ying

    2017-02-15

    Neuroimaging studies have demonstrated that the major depression disorder would increase the risk of dementia in the older with amnestic cognitive impairment. We used granger causality analysis algorithm to explore the amygdala- and hippocampus-based directional connectivity patterns in 12 patients with major depression disorder and amnestic cognitive impairment (mean age: 69.5 ± 10.3 years), 13 amnestic cognitive impairment patients (mean age: 72.7 ± 8.5 years) and 14 healthy controls (mean age: 64.7 ± 7.0 years). Compared with amnestic cognitive impairment patients and control groups respectively, the patients with both major depression disorder and amnestic cognitive impairment displayed increased effective connectivity from the right amygdala to the right lingual and calcarine gyrus, as well as to the bilateral supplementary motor areas. Meanwhile, the patients with both major depression disorder and amnestic cognitive impairment had enhanced effective connectivity from the left superior parietal gyrus, superior and middle occipital gyrus to the left hippocampus, the z values of which was also correlated with the scores of mini-mental state examination and auditory verbal learning test-immediate recall. Our findings indicated that the directional effective connectivity of right amygdala - occipital-parietal lobe - left hippocampus might be the pathway by which major depression disorder inhibited the brain activity in patients with amnestic cognitive impairment.

  4. Developmental iodine deficiency and hypothyroidism impair neural development in rat hippocampus: involvement of doublecortin and NCAM-180

    PubMed Central

    2010-01-01

    Background Developmental iodine deficiency results in inadequate thyroid hormone (TH), which damages the hippocampus. Here, we explored the roles of hippocampal doublecortin and neural cell adhesion molecule (NCAM)-180 in developmental iodine deficiency and hypothyroidism. Methods Two developmental rat models were established with either an iodine-deficient diet, or propylthiouracil (PTU)-adulterated water (5 ppm or 15 ppm) to impair thyroid function, in pregnant rats from gestational day 6 until postnatal day (PN) 28. Silver-stained neurons and protein levels of doublecortin and NCAM-180 in several hippocampal subregions were assessed on PN14, PN21, PN28, and PN42. Results The results show that nerve fibers in iodine-deficient and 15 ppm PTU-treated rats were injured on PN28 and PN42. Downregulation of doublecortin and upregulation of NCAM-180 were observed in iodine-deficient and 15 ppm PTU-treated rats from PN14 on. These alterations were irreversible by the restoration of serum TH concentrations on PN42. Conclusion Developmental iodine deficiency and hypothyroidism impair the expression of doublecortin and NCAM-180, leading to nerve fiber malfunction and thus impairments in hippocampal development. PMID:20412599

  5. Developmental iodine deficiency and hypothyroidism impair neural development in rat hippocampus: involvement of doublecortin and NCAM-180.

    PubMed

    Gong, Jian; Liu, Wanyang; Dong, Jing; Wang, Yi; Xu, Hongde; Wei, Wei; Zhong, Jiapeng; Xi, Qi; Chen, Jie

    2010-04-23

    Developmental iodine deficiency results in inadequate thyroid hormone (TH), which damages the hippocampus. Here, we explored the roles of hippocampal doublecortin and neural cell adhesion molecule (NCAM)-180 in developmental iodine deficiency and hypothyroidism. Two developmental rat models were established with either an iodine-deficient diet, or propylthiouracil (PTU)-adulterated water (5 ppm or 15 ppm) to impair thyroid function, in pregnant rats from gestational day 6 until postnatal day (PN) 28. Silver-stained neurons and protein levels of doublecortin and NCAM-180 in several hippocampal subregions were assessed on PN14, PN21, PN28, and PN42. The results show that nerve fibers in iodine-deficient and 15 ppm PTU-treated rats were injured on PN28 and PN42. Downregulation of doublecortin and upregulation of NCAM-180 were observed in iodine-deficient and 15 ppm PTU-treated rats from PN14 on. These alterations were irreversible by the restoration of serum TH concentrations on PN42. Developmental iodine deficiency and hypothyroidism impair the expression of doublecortin and NCAM-180, leading to nerve fiber malfunction and thus impairments in hippocampal development.

  6. Hypertension impairs hippocampus-related adult neurogenesis, CA1 neuron dendritic arborization and long-term memory.

    PubMed

    Shih, Y-H; Tsai, S-F; Huang, S-H; Chiang, Y-T; Hughes, M W; Wu, S-Y; Lee, C-W; Yang, T-T; Kuo, Y-M

    2016-05-13

    Hypertension is associated with neurodegenerative diseases and cognitive impairment. Several studies using spontaneous hypertensive rats to study the effect of hypertension on memory performance and adult hippocampal neurogenesis have reached inconsistent conclusions. The contradictory findings may be related to the genetic variability of spontaneous hypertensive rats due to the conventional breeding practices. The objective of this study is to examine the effect of hypertension on hippocampal structure and function in isogenic mice. Hypertension was induced by the '2 kidneys, 1 clip' method (2K1C) which constricted one of the two renal arteries. The blood pressures of 2K1C mice were higher than the sham group on post-operation day 7 and remained high up to day 28. Mice with 2K1C-induced hypertension had impaired long-term, but not short-term, memory. Dendritic complexity of CA1 neurons and hippocampal neurogenesis were reduced by 2K1C-induced hypertension on post-operation day 28. Furthermore, 2K1C decreased the levels of hippocampal brain-derived neurotrophic factor, while blood vessel density and activation status of astrocytes and microglia were not affected. In conclusion, hypertension impairs hippocampus-associated long-term memory, dendritic arborization and neurogenesis, which may be caused by down-regulation of brain-derived neurotrophic factor signaling pathways.

  7. Hyperammonemia impairs NMDA receptor-dependent long-term potentiation in the CA1 of rat hippocampus in vitro.

    PubMed

    Muñoz, M D; Monfort, P; Gaztelu, J M; Felipo, V

    2000-04-01

    Hyperammonemia is considered the main factor responsible for the neurological and cognitive alterations found in hepatic encephalopathy and in patients with congenital deficiencies of the urea cycle enzymes. The underlying mechanisms remain unclear. Chronic moderate hyperammonemia reduces nitric oxide-induced activation of soluble guanylate cyclase and glutamate-induced formation of cGMP. NMDA receptor-associated transduction pathways, including activation of soluble guanylate cyclase, are involved in the induction of long-term potentiation (LTP), a phenomenon that is considered to be the molecular basis for some forms of memory and learning. Using an animal model we show that chronic hyperammonemia significantly reduces the degree of long-term potentiation induced in the CA1 of hippocampus slices (200% increase in control and 50% increase in slices of hyperammonemic animals). Also, addition of 1 mM ammonia impaired the maintenance of non-decremental LTP. The LTP impairment could be involved in the intellectual impairment present in chronic hepatocerebral disorders associated with hyperammonemia.

  8. Caffeine consumption prevents diabetes-induced memory impairment and synaptotoxicity in the hippocampus of NONcZNO10/LTJ mice.

    PubMed

    Duarte, João M N; Agostinho, Paula M; Carvalho, Rui A; Cunha, Rodrigo A

    2012-01-01

    Diabetic conditions are associated with modified brain function, namely with cognitive deficits, through largely undetermined processes. More than understanding the underlying mechanism, it is important to devise novel strategies to alleviate diabetes-induced cognitive deficits. Caffeine (a mixed antagonist of adenosine A(1) and A(2A) receptors) emerges as a promising candidate since caffeine consumption reduces the risk of diabetes and effectively prevents memory deficits caused by different noxious stimuli. Thus, we took advantage of a novel animal model of type 2 diabetes to investigate the behavioural, neurochemical and morphological modifications present in the hippocampus and tested if caffeine consumption might prevent these changes. We used a model closely mimicking the human type 2 diabetes condition, NONcNZO10/LtJ mice, which become diabetic at 7-11 months when kept under an 11% fat diet. Caffeine (1 g/l) was applied in the drinking water from 7 months onwards. Diabetic mice displayed a decreased spontaneous alternation in the Y-maze accompanied by a decreased density of nerve terminal markers (synaptophysin, SNAP25), mainly glutamatergic (vesicular glutamate transporters), and increased astrogliosis (GFAP immunoreactivity) compared to their wild type littermates kept under the same diet. Furthermore, diabetic mice displayed up-regulated A(2A) receptors and down-regulated A(1) receptors in the hippocampus. Caffeine consumption restored memory performance and abrogated the diabetes-induced loss of nerve terminals and astrogliosis. These results provide the first evidence that type 2 diabetic mice display a loss of nerve terminal markers and astrogliosis, which is associated with memory impairment; furthermore, caffeine consumption prevents synaptic dysfunction and astrogliosis as well as memory impairment in type 2 diabetes.

  9. Caffeine Consumption Prevents Diabetes-Induced Memory Impairment and Synaptotoxicity in the Hippocampus of NONcZNO10/LTJ Mice

    PubMed Central

    Duarte, João M. N.; Agostinho, Paula M.; Carvalho, Rui A.; Cunha, Rodrigo A.

    2012-01-01

    Diabetic conditions are associated with modified brain function, namely with cognitive deficits, through largely undetermined processes. More than understanding the underlying mechanism, it is important to devise novel strategies to alleviate diabetes-induced cognitive deficits. Caffeine (a mixed antagonist of adenosine A1 and A2A receptors) emerges as a promising candidate since caffeine consumption reduces the risk of diabetes and effectively prevents memory deficits caused by different noxious stimuli. Thus, we took advantage of a novel animal model of type 2 diabetes to investigate the behavioural, neurochemical and morphological modifications present in the hippocampus and tested if caffeine consumption might prevent these changes. We used a model closely mimicking the human type 2 diabetes condition, NONcNZO10/LtJ mice, which become diabetic at 7–11 months when kept under an 11% fat diet. Caffeine (1 g/l) was applied in the drinking water from 7 months onwards. Diabetic mice displayed a decreased spontaneous alternation in the Y-maze accompanied by a decreased density of nerve terminal markers (synaptophysin, SNAP25), mainly glutamatergic (vesicular glutamate transporters), and increased astrogliosis (GFAP immunoreactivity) compared to their wild type littermates kept under the same diet. Furthermore, diabetic mice displayed up-regulated A2A receptors and down-regulated A1 receptors in the hippocampus. Caffeine consumption restored memory performance and abrogated the diabetes-induced loss of nerve terminals and astrogliosis. These results provide the first evidence that type 2 diabetic mice display a loss of nerve terminal markers and astrogliosis, which is associated with memory impairment; furthermore, caffeine consumption prevents synaptic dysfunction and astrogliosis as well as memory impairment in type 2 diabetes. PMID:22514596

  10. Stress induces altered CRE/CREB pathway activity and BDNF expression in the hippocampus of glucocorticoid receptor-impaired mice.

    PubMed

    Alboni, Silvia; Tascedda, Fabio; Corsini, Daniela; Benatti, Cristina; Caggia, Federica; Capone, Giacomo; Barden, Nicholas; Blom, Joan M C; Brunello, Nicoletta

    2011-06-01

    The gene coding for the neurotrophin Brain-Derived Neurotrophic Factor (BDNF) is a stress-responsive gene. Changes in its expression may underlie some of the pathological effects of stress-related disorders like depression. Data on the stress-induced regulation of the expression of BDNF in pathological conditions are rare because often research is conducted using healthy animals. In our experiments, we used transgenic mice with glucocorticoid receptor impaired (GR-i) expression in the hypothalamus created as a tool to study the neuroendocrine changes occurring in stress-related disorders. First, under basal condition, GR-i mice displayed lower levels of BDNF exons IX and IV and decreased CRE(BDNF) binding activity with respect to wild-type (WT) mice in the hippocampus. Then, we exposed GR-i and WT mice to an acute restraint stress (ARS) to test the hypothesis that GR-i mice display: 1] different ARS induced expression of BDNF, and 2] altered activation of signaling pathways implicated in regulating BDNF gene expression in the hippocampus with respect to WT mice. Results indicate that ARS enhanced BDNF mRNA expression mainly in the CA3 hippocampal sub-region of GR-i mice in the presence of enhanced levels of pro-BDNF protein, while no effect was observed in WT mice. Moreover, ARS reduced CREB signaling and binding to the BDNF promoter in GR-i mice but enhanced signaling and binding, possibly through ERK1/2 activation, in WT mice. Thus, life-long central GR dysfunction resulted in an altered sensitivity at the transcriptional level that may underlie an impaired response to an acute psycho-physical stress. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.

  11. MDMA increases glutamate release and reduces parvalbumin-positive GABAergic cells in the dorsal hippocampus of the rat: role of cyclooxygenase.

    PubMed

    Anneken, John H; Cunningham, Jacobi I; Collins, Stuart A; Yamamoto, Bryan K; Gudelsky, Gary A

    2013-03-01

    3,4-Methylenedioxymethamphetamine (MDMA; Ecstasy) is a popular drug of abuse with well-documented acute effects on serotonergic, dopaminergic, and cholinergic transmitter systems, as well as evidence of long-term disruption of serotoninergic systems in the rat brain. Recently, it was demonstrated that MDMA evokes a delayed and sustained increase in glutamate release in the hippocampus. The purpose of the present study was to determine the role of inflammatory mediators in the MDMA-induced increase in glutamate release, as well as the contribution of inflammatory pathways in the persistent neurochemical toxicity associated with repeated MDMA treatment. Treatment with the non-selective cyclooxygenase (COX) inhibitor ketoprofen and the COX-2 selective inhibitor nimesulide attenuated the increase in extracellular glutamate in the hippocampus evoked by repeated MDMA exposure (10 mg/kg, i.p., every 2 h); no attenuation was observed in rats treated with the COX-1 selective inhibitor piroxicam. Reverse dialysis of a major product of COX activity, prostaglandin E2, also resulted in a significant increase in extracellular glutamate in the hippocampus . Repeated exposure to MDMA diminished the number of parvalbumin-positive GABA interneurons in the dentate gyrus of the hippocampus, an effect that was attenuated by ketoprofen treatment. However, COX inhibition with ketoprofen did not prevent the long-term depletion of 5-HT in the hippocampus evoked by MDMA treatment. These data are supportive of the view that cyclooxygenase activity contributes to the mechanism underlying both the increased release of glutamate and decreased number of GABA interneurons in the rat hippocampus produced by repeated MDMA exposure.

  12. Vitamin B1-deficient mice show impairment of hippocampus-dependent memory formation and loss of hippocampal neurons and dendritic spines: potential microendophenotypes of Wernicke–Korsakoff syndrome

    PubMed Central

    Inaba, Hiroyoshi; Kishimoto, Takuya; Oishi, Satoru; Nagata, Kan; Hasegawa, Shunsuke; Watanabe, Tamae; Kida, Satoshi

    2016-01-01

    Patients with severe Wernicke–Korsakoff syndrome (WKS) associated with vitamin B1 (thiamine) deficiency (TD) show enduring impairment of memory formation. The mechanisms of memory impairment induced by TD remain unknown. Here, we show that hippocampal degeneration is a potential microendophenotype (an endophenotype of brain disease at the cellular and synaptic levels) of WKS in pyrithiamine-induced thiamine deficiency (PTD) mice, a rodent model of WKS. PTD mice show deficits in the hippocampus-dependent memory formation, although they show normal hippocampus-independent memory. Similarly with WKS, impairments in memory formation did not recover even at 6 months after treatment with PTD. Importantly, PTD mice exhibit a decrease in neurons in the CA1, CA3, and dentate gyrus (DG) regions of the hippocampus and reduced density of wide dendritic spines in the DG. Our findings suggest that TD induces hippocampal degeneration, including the loss of neurons and spines, thereby leading to enduring impairment of hippocampus-dependent memory formation. PMID:27576603

  13. Vitamin B1-deficient mice show impairment of hippocampus-dependent memory formation and loss of hippocampal neurons and dendritic spines: potential microendophenotypes of Wernicke-Korsakoff syndrome.

    PubMed

    Inaba, Hiroyoshi; Kishimoto, Takuya; Oishi, Satoru; Nagata, Kan; Hasegawa, Shunsuke; Watanabe, Tamae; Kida, Satoshi

    2016-12-01

    Patients with severe Wernicke-Korsakoff syndrome (WKS) associated with vitamin B1 (thiamine) deficiency (TD) show enduring impairment of memory formation. The mechanisms of memory impairment induced by TD remain unknown. Here, we show that hippocampal degeneration is a potential microendophenotype (an endophenotype of brain disease at the cellular and synaptic levels) of WKS in pyrithiamine-induced thiamine deficiency (PTD) mice, a rodent model of WKS. PTD mice show deficits in the hippocampus-dependent memory formation, although they show normal hippocampus-independent memory. Similarly with WKS, impairments in memory formation did not recover even at 6 months after treatment with PTD. Importantly, PTD mice exhibit a decrease in neurons in the CA1, CA3, and dentate gyrus (DG) regions of the hippocampus and reduced density of wide dendritic spines in the DG. Our findings suggest that TD induces hippocampal degeneration, including the loss of neurons and spines, thereby leading to enduring impairment of hippocampus-dependent memory formation.

  14. Impaired mitochondrial respiration and protein nitration in the rat hippocampus after acute inhalation of combustion smoke

    SciTech Connect

    Lee, Heung M.; Reed, Jason; Greeley, George H.; Englander, Ella W.

    2009-03-01

    Survivors of massive inhalation of combustion smoke endure critical injuries, including lasting neurological complications. We have previously reported that acute inhalation of combustion smoke disrupts the nitric oxide homeostasis in the rat brain. In this study, we extend our findings and report that a 30-minute exposure of awake rats to ambient wood combustion smoke induces protein nitration in the rat hippocampus and that mitochondrial proteins are a sensitive nitration target in this setting. Mitochondria are central to energy metabolism and cellular signaling and are critical to proper cell function. Here, analyses of the mitochondrial proteome showed elevated protein nitration in the course of a 24-hour recovery following exposure to smoke. Mass spectrometry identification of several significantly nitrated mitochondrial proteins revealed diverse functions and involvement in central aspects of mitochondrial physiology. The nitrated proteins include the ubiquitous mitochondrial creatine kinase, F1-ATP synthase {alpha} subunit, dihydrolipoamide dehydrogenase (E3), succinate dehydrogenase Fp subunit, and voltage-dependent anion channel (VDAC1) protein. Furthermore, acute exposure to combustion smoke significantly compromised the respiratory capacity of hippocampal mitochondria. Importantly, elevated protein nitration and reduced mitochondrial respiration in the hippocampus persisted beyond the time required for restoration of normal oxygen and carboxyhemoglobin blood levels after the cessation of exposure to smoke. Thus, the time frame for intensification of the various smoke-induced effects differs between blood and brain tissues. Taken together, our findings suggest that nitration of essential mitochondrial proteins may contribute to the reduction in mitochondrial respiratory capacity and underlie, in part, the brain pathophysiology after acute inhalation of combustion smoke.

  15. Impaired mitochondrial respiration and protein nitration in the rat hippocampus after acute inhalation of combustion smoke.

    PubMed

    Lee, Heung M; Reed, Jason; Greeley, George H; Englander, Ella W

    2009-03-01

    Survivors of massive inhalation of combustion smoke endure critical injuries, including lasting neurological complications. We have previously reported that acute inhalation of combustion smoke disrupts the nitric oxide homeostasis in the rat brain. In this study, we extend our findings and report that a 30-minute exposure of awake rats to ambient wood combustion smoke induces protein nitration in the rat hippocampus and that mitochondrial proteins are a sensitive nitration target in this setting. Mitochondria are central to energy metabolism and cellular signaling and are critical to proper cell function. Here, analyses of the mitochondrial proteome showed elevated protein nitration in the course of a 24-hour recovery following exposure to smoke. Mass spectrometry identification of several significantly nitrated mitochondrial proteins revealed diverse functions and involvement in central aspects of mitochondrial physiology. The nitrated proteins include the ubiquitous mitochondrial creatine kinase, F1-ATP synthase alpha subunit, dihydrolipoamide dehydrogenase (E3), succinate dehydrogenase Fp subunit, and voltage-dependent anion channel (VDAC1) protein. Furthermore, acute exposure to combustion smoke significantly compromised the respiratory capacity of hippocampal mitochondria. Importantly, elevated protein nitration and reduced mitochondrial respiration in the hippocampus persisted beyond the time required for restoration of normal oxygen and carboxyhemoglobin blood levels after the cessation of exposure to smoke. Thus, the time frame for intensification of the various smoke-induced effects differs between blood and brain tissues. Taken together, our findings suggest that nitration of essential mitochondrial proteins may contribute to the reduction in mitochondrial respiratory capacity and underlie, in part, the brain pathophysiology after acute inhalation of combustion smoke.

  16. Detection of histone acetylation levels in the dorsal hippocampus reveals early tagging on specific residues of H2B and H4 histones in response to learning.

    PubMed

    Bousiges, Olivier; Neidl, Romain; Majchrzak, Monique; Muller, Marc-Antoine; Barbelivien, Alexandra; Pereira de Vasconcelos, Anne; Schneider, Anne; Loeffler, Jean-Philippe; Cassel, Jean-Christophe; Boutillier, Anne-Laurence

    2013-01-01

    The recent literature provides evidence that epigenetic mechanisms such as DNA methylation and histone modification are crucial to gene transcription linked to synaptic plasticity in the mammalian brain--notably in the hippocampus--and memory formation. We measured global histone acetylation levels in the rat hippocampus at an early stage of spatial or fear memory formation. We found that H3, H4 and H2B underwent differential acetylation at specific sites depending on whether rats had been exposed to the context of a task without having to learn or had to learn about a place or fear therein: H3K9K14 acetylation was mostly responsive to any experimental conditions compared to naive animals, whereas H2B N-terminus and H4K12 acetylations were mostly associated with memory for either spatial or fear learning. Altogether, these data suggest that behavior/experience-dependent changes differently regulate specific acetylation modifications of histones in the hippocampus, depending on whether a memory trace is established or not: tagging of H3K9K14 could be associated with perception/processing of testing-related manipulations and context, thereby enhancing chromatin accessibility, while tagging of H2B N-terminus tail and H4K12 could be more closely associated with the formation of memories requiring an engagement of the hippocampus.

  17. Early Exposure to Ketamine Impairs Axonal Pruning in Developing Mouse Hippocampus.

    PubMed

    Obradovic, Aleksandar Lj; Atluri, Navya; Massara, Lorenza Dalla; Oklopcic, Azra; Todorovic, Nikola S; Katta, Gaurav; Osuru, Hari P; Jevtovic-Todorovic, Vesna

    2017-08-24

    Mounting evidence suggests that prolonged exposure to general anesthesia (GA) during brain synaptogenesis damages the immature neurons and results in long-term neurocognitive impairments. Importantly, synaptogenesis relies on timely axon pruning to select axons that participate in active neural circuit formation. This process is in part dependent on proper homeostasis of neurotrophic factors, in particular brain-derived neurotrophic factor (BDNF). We set out to examine how GA may modulate axon maintenance and pruning and focused on the role of BDNF. We exposed post-natal day (PND)7 mice to ketamine using a well-established dosing regimen known to induce significant developmental neurotoxicity. We performed morphometric analyses of the infrapyramidal bundle (IPB) since IPB is known to undergo intense developmental modeling and as such is commonly used as a well-established model of in vivo pruning in rodents. When IPB remodeling was followed from PND10 until PND65, we noted a delay in axonal pruning in ketamine-treated animals when compared to controls; this impairment coincided with ketamine-induced downregulation in BDNF protein expression and maturation suggesting two conclusions: a surge in BDNF protein expression "signals" intense IPB pruning in control animals and ketamine-induced downregulation of BDNF synthesis and maturation could contribute to impaired IPB pruning. We conclude that the combined effects on BDNF homeostasis and impaired axon pruning may in part explain ketamine-induced impairment of neuronal circuitry formation.

  18. Fragmentation of Rapid Eye Movement and Nonrapid Eye Movement Sleep without Total Sleep Loss Impairs Hippocampus-Dependent Fear Memory Consolidation.

    PubMed

    Lee, Michael L; Katsuyama, Ângela M; Duge, Leanne S; Sriram, Chaitra; Krushelnytskyy, Mykhaylo; Kim, Jeansok J; de la Iglesia, Horacio O

    2016-11-01

    Sleep is important for consolidation of hippocampus-dependent memories. It is hypothesized that the temporal sequence of nonrapid eye movement (NREM) sleep and rapid eye movement (REM) sleep is critical for the weakening of nonadaptive memories and the subsequent transfer of memories temporarily stored in the hippocampus to more permanent memories in the neocortex. A great body of evidence supporting this hypothesis relies on behavioral, pharmacological, neural, and/or genetic manipulations that induce sleep deprivation or stage-specific sleep deprivation. We exploit an experimental model of circadian desynchrony in which intact animals are not deprived of any sleep stage but show fragmentation of REM and NREM sleep within nonfragmented sleep bouts. We test the hypothesis that the shortening of NREM and REM sleep durations post-training will impair memory consolidation irrespective of total sleep duration. When circadian-desynchronized animals are trained in a hippocampus-dependent contextual fear-conditioning task they show normal short-term memory but impaired long-term memory consolidation. This impairment in memory consolidation is positively associated with the post-training fragmentation of REM and NREM sleep but is not significantly associated with the fragmentation of total sleep or the total amount of delta activity. We also show that the sleep stage fragmentation resulting from circadian desynchrony has no effect on hippocampus-dependent spatial memory and no effect on hippocampus-independent cued fear-conditioning memory. Our findings in an intact animal model, in which sleep deprivation is not a confounding factor, support the hypothesis that the stereotypic sequence and duration of sleep stages play a specific role in long-term hippocampus-dependent fear memory consolidation.

  19. Selective cholinergic depletion in medial septum leads to impaired long term potentiation and glutamatergic synaptic currents in the hippocampus.

    PubMed

    Kanju, Patrick M; Parameshwaran, Kodeeswaran; Sims-Robinson, Catrina; Uthayathas, Subramaniam; Josephson, Eleanor M; Rajakumar, Nagalingam; Dhanasekaran, Muralikrishnan; Suppiramaniam, Vishnu

    2012-01-01

    Cholinergic depletion in the medial septum (MS) is associated with impaired hippocampal-dependent learning and memory. Here we investigated whether long term potentiation (LTP) and synaptic currents, mediated by alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) and N-methyl-D-aspartate (NMDA) receptors in the CA1 hippocampal region, are affected following cholinergic lesions of the MS. Stereotaxic intra-medioseptal infusions of a selective immunotoxin, 192-saporin, against cholinergic neurons or sterile saline were made in adult rats. Four days after infusions, hippocampal slices were made and LTP, whole cell, and single channel (AMPA or NMDA receptor) currents were recorded. Results demonstrated impairment in the induction and expression of LTP in lesioned rats. Lesioned rats also showed decreases in synaptic currents from CA1 pyramidal cells and synaptosomal single channels of AMPA and NMDA receptors. Our results suggest that MS cholinergic afferents modulate LTP and glutamatergic currents in the CA1 region of the hippocampus, providing a potential synaptic mechanism for the learning and memory deficits observed in the rodent model of selective MS cholinergic lesioning.

  20. Genetic Disruption of the Core Circadian Clock Impairs Hippocampus-Dependent Memory

    ERIC Educational Resources Information Center

    Wardlaw, Sarah M.; Phan, Trongha X.; Saraf, Amit; Chen, Xuanmao; Storm, Daniel R.

    2014-01-01

    Perturbing the circadian system by electrolytically lesioning the suprachiasmatic nucleus (SCN) or varying the environmental light:dark schedule impairs memory, suggesting that memory depends on the circadian system. We used a genetic approach to evaluate the role of the molecular clock in memory. Bmal1[superscript -/-] mice, which are arrhythmic…

  1. Gamma Radiation (5-10 Gy) Impairs Neuronal Function in the Guinea Pig Hippocampus

    DTIC Science & Technology

    1993-01-01

    induced damage sively demonstrates that neuronal function is impaired by in the central nervous system. In Cytotoxic Insult to Tissues: Effects low... theophylline re- Schwartz, The role of arachidonic acid metabolites in signal trans- sponse with morphology. Radiat. Res. 117, 419-432 (1986

  2. Genetic Disruption of the Core Circadian Clock Impairs Hippocampus-Dependent Memory

    ERIC Educational Resources Information Center

    Wardlaw, Sarah M.; Phan, Trongha X.; Saraf, Amit; Chen, Xuanmao; Storm, Daniel R.

    2014-01-01

    Perturbing the circadian system by electrolytically lesioning the suprachiasmatic nucleus (SCN) or varying the environmental light:dark schedule impairs memory, suggesting that memory depends on the circadian system. We used a genetic approach to evaluate the role of the molecular clock in memory. Bmal1[superscript -/-] mice, which are arrhythmic…

  3. Nicotine-prevented learning and memory impairment in REM sleep-deprived rat is modulated by DREAM protein in the hippocampus.

    PubMed

    Abd Rashid, Norlinda; Hapidin, Hermizi; Abdullah, Hasmah; Ismail, Zalina; Long, Idris

    2017-06-01

    REM sleep deprivation is associated with impairment in learning and memory, and nicotine treatment has been shown to attenuate this effect. Recent studies have demonstrated the importance of DREAM protein in learning and memory processes. This study investigates the association of DREAM protein in REM sleep-deprived rats hippocampus upon nicotine treatment. Male Sprague Dawley rats were subjected to normal condition, REM sleep deprivation and control wide platform condition for 72 hr. During this procedure, saline or nicotine (1 mg/kg) was given subcutaneously twice a day. Then, Morris water maze (MWM) test was used to assess learning and memory performance of the rats. The rats were sacrificed and the brain was harvested for immunohistochemistry and Western blot analysis. MWM test found that REM sleep deprivation significantly impaired learning and memory performance without defect in locomotor function associated with a significant increase in hippocampus DREAM protein expression in CA1, CA2, CA3, and DG regions and the mean relative level of DREAM protein compared to other experimental groups. Treatment with acute nicotine significantly prevented these effects and decreased expression of DREAM protein in all the hippocampus regions but only slightly reduce the mean relative level of DREAM protein. This study suggests that changes in DREAM protein expression in CA1, CA2, CA3, and DG regions of rat's hippocampus and mean relative level of DREAM protein may involve in the mechanism of nicotine treatment-prevented REM sleep deprivation-induced learning and memory impairment in rats.

  4. Increasing Acetylcholine Levels in the Hippocampus or Entorhinal Cortex Reverses the Impairing Effects of Septal GABA Receptor Activation on Spontaneous Alternation

    PubMed Central

    Degroot, Aldemar; Parent, Marise B.

    2000-01-01

    Intra-septal infusions of the γ-aminobutyric acid (GABA) agonist muscimol impair learning and memory in a variety of tasks. This experiment determined whether hippocampal or entorhinal infusions of the acetylcholinesterase inhibitor physostigmine would reverse such impairing effects on spontaneous alternation performance, a measure of spatial working memory. Male Sprague-Dawley rats were given intra-septal infusions of vehicle or muscimol (1 nmole/0.5 μL) combined with unilateral intra-hippocampal or intra-entorhinal infusions of vehicle or physostigmine (10 μg/μL for the hippocampus; 7.5 μg/μL or 1.875 μg/0.25 μL for the entorhinal cortex). Fifteen minutes later, spontaneous alternation performance was assessed. The results indicated that intra-septal infusions of muscimol significantly decreased percentage-of-alternation scores, whereas intra-hippocampal or intra-entorhinal infusions of physostigmine had no effect. More importantly, intra-hippocampal or intra-entorhinal infusions of physostigmine, at doses that did not influence performance when administered alone, completely reversed the impairing effects of the muscimol infusions. These findings indicate that increasing cholinergic levels in the hippocampus or entorhinal cortex is sufficient to reverse the impairing effects of septal GABA receptor activation and support the hypothesis that the impairing effects of septal GABAergic activity involve cholinergic processes in the hippocampus and the entorhinal cortex. PMID:11040261

  5. Antidepressants that inhibit both serotonin and norepinephrine reuptake impair long-term potentiation in hippocampus

    PubMed Central

    Cooke, Jennifer D.; Cavender, Hannah M.; Lima, Hope K.; Grover, Lawrence M.

    2014-01-01

    Rationale Monoamine reuptake inhibitors can stimulate expression of brain-derived neurotrophic factor (BDNF) and alter long-term potentiation (LTP), a widely used model for the synaptic mechanisms that underlie memory formation. BDNF expression is up-regulated during LTP, and BDNF in turn positively modulates LTP. Previously, we found that treatment with venlafaxine, a serotonin and norepinephrine reuptake inhibitor (SNRI), but not citalopram, a selective serotonin reuptake inhibitor (SSRI) reduced LTP in hippocampal area CA1 without changing hippocampal BDNF protein expression. Objectives We tested the hypothesis that combined serotonin and norepinephrine reuptake inhibition is necessary for LTP impairment, and we reexamined the potential role of BNDF by testing for region-specific changes in areas CA1, CA3 and dentate gyrus. We also tested whether early events in the LTP signaling pathway were altered to impair LTP. Methods Animals were treated for 21 days with venlafaxine, imipramine, fluoxetine, or maprotiline. In vitro hippocampal slices were used for electrophysiological measurements. Protein expression was measured by enzyme-linked immunosorbent assay (ELISA) and western blotting. Results LTP was impaired only following treatment with combined serotonin and norepinephrine reuptake inhibitors (venlafaxine, imipramine) but not with selective serotonin (fluoxetine) or norepinephrine (maprotiline) reuptake inhibitors. BDNF protein expression was not altered by venlafaxine or imipramine treatment, nor were postsynaptic depolarization during LTP inducing stimulation or synaptic membrane NMDA receptor subunit expression affected. Conclusions LTP is impaired by chronic treatment with antidepressant that inhibit both serotonin and norepinephrine reuptake; this impairment results from changes that are downstream of postsynaptic depolarization and calcium-influx. PMID:24781518

  6. Status Epilepticus Impairs Synaptic Plasticity in Rat Hippocampus and Is Followed by Changes in Expression of NMDA Receptors.

    PubMed

    Postnikova, T Y; Zubareva, O E; Kovalenko, A A; Kim, K K; Magazanik, L G; Zaitsev, A V

    2017-03-01

    Cognitive deficits and memory loss are frequent in patients with temporal lobe epilepsy. Persistent changes in synaptic efficacy are considered as a cellular substrate underlying memory processes. Electrophysiological studies have shown that the properties of short-term and long-term synaptic plasticity in the cortex and hippocampus may undergo substantial changes after seizures. However, the neural mechanisms responsible for these changes are not clear. In this study, we investigated the properties of short-term and long-term synaptic plasticity in rat hippocampal slices 24 h after pentylenetetrazole (PTZ)-induced status epilepticus. We found that the induction of long-term potentiation (LTP) in CA1 pyramidal cells is reduced compared to the control, while short-term facilitation is increased. The experimental results do not support the hypothesis that status epilepticus leads to background potentiation of hippocampal synapses and further LTP induction becomes weaker due to occlusion, as the dependence of synaptic responses on the strength of input stimulation was not different in the control and experimental animals. The decrease in LTP can be caused by impairment of molecular mechanisms of neuronal plasticity, including those associated with NMDA receptors and/or changes in their subunit composition. Real-time PCR demonstrated significant increases in the expression of GluN1 and GluN2A subunits 3 h after PTZ-induced status epilepticus. The overexpression of obligate GluN1 subunit suggests an increase in the total number of NMDA receptors in the hippocampus. A 3-fold increase in the expression of the GluN2B subunit observed 24 h after PTZ-induced status epilepticus might be indicative of an increase in the proportion of GluN2B-containing NMDA receptors. Increased expression of the GluN2B subunit may be a cause for reducing the magnitude of LTP at hippocampal synapses after status epilepticus.

  7. Estradiol replacement enhances fear memory formation, impairs extinction and reduces COMT expression levels in the hippocampus of ovariectomized female mice.

    PubMed

    McDermott, Carmel M; Liu, Dan; Ade, Catherine; Schrader, Laura A

    2015-02-01

    Females experience depression, posttraumatic stress disorder (PTSD), and anxiety disorders at approximately twice the rate of males, but the mechanisms underlying this difference remain undefined. The effect of sex hormones on neural substrates presents a possible mechanism. We investigated the effect of ovariectomy at two ages, before puberty and in adulthood, and 17β-estradiol (E2) replacement administered chronically in drinking water on anxiety level, fear memory formation, and extinction. Based on previous studies, we hypothesized that estradiol replacement would impair fear memory formation and enhance extinction rate. Females, age 4 weeks and 10 weeks, were divided randomly into 4 groups; sham surgery, OVX, OVX+low E2 (200nM), and OVX+high E2 (1000nM). Chronic treatment with high levels of E2 significantly increased anxiety levels measured in the elevated plus maze. In both age groups, high levels of E2 significantly increased contextual fear memory but had no effect on cued fear memory. In addition, high E2 decreased the rate of extinction in both ages. Finally, catechol-O-methyltransferase (COMT) is important for regulation of catecholamine levels, which play a role in fear memory formation and extinction. COMT expression in the hippocampus was significantly reduced by high E2 replacement, implying increased catecholamine levels in the hippocampus of high E2 mice. These results suggest that estradiol enhanced fear memory formation, and inhibited fear memory extinction, possibly stabilizing the fear memory in female mice. This study has implications for a neurobiological mechanism for PTSD and anxiety disorders. Copyright © 2014 Elsevier Inc. All rights reserved.

  8. The effects of doxepin on stress-induced learning, memory impairments, and TNF-α level in the rat hippocampus

    PubMed Central

    Azadbakht, Ali Ahmad; Radahmadi, Maryam; Javanmard, Shaghayegh Haghjooye; Reisi, Parham

    2015-01-01

    Stress has a profound impact on the nervous system and causes cognitive problems that are partly related to the inflammatory effects. Besides influencing the content of neurotransmitters, antidepressants such as doxepin are likely to have anti-inflammatory, anti-oxidative, and anti-apoptotic effects. Therefore, the present study investigated the effects of doxepin on passive avoidance learning and the levels of tumor necrosis factor-alpha (TNF-α) in the rat hippocampus following repeated restraint stress. Male Wistar rats were divided into five groups. Chronic stress was induced by keeping animals within an adjustable restraint chamber for 6 h every day for 21 successive days. In stress-doxepin group, stressed rats were given 1, 5 and 10 mg/kg of doxepin intraperitoneally (i.p) for 21 days and before placing them in restraint chamber. Healthy animals who served as control group and stressed rats received normal saline i.p. For evaluation of learning and memory, initial latency and step-through latency were determined using passive avoidance learning test. TNF-α levels were measured in hippocampus by enzyme-linked immunosorbant assay (ELISA) at the end of experiment. Induced stress considerably decreased the step through latencies in the rats (P<0.05) but doxepin administration prevented these changes. Stress-doxepin groups did not reveal any differences compared to control group at any given doses. TNF-α level was increased significantly (P<0.05) in stress group. Only the low dose of doxepin (1 mg/kg) decreased TNF-α level. The present findings indicated that learning and memory are impaired in stressful conditions and doxepin prevented memory deficit. It seems that inflammation may involve in induced stress memory deficits, and that doxepin is helpful in alleviating the neural complications due to stress. PMID:26752995

  9. The effects of doxepin on stress-induced learning, memory impairments, and TNF-α level in the rat hippocampus.

    PubMed

    Azadbakht, Ali Ahmad; Radahmadi, Maryam; Javanmard, Shaghayegh Haghjooye; Reisi, Parham

    2015-01-01

    Stress has a profound impact on the nervous system and causes cognitive problems that are partly related to the inflammatory effects. Besides influencing the content of neurotransmitters, antidepressants such as doxepin are likely to have anti-inflammatory, anti-oxidative, and anti-apoptotic effects. Therefore, the present study investigated the effects of doxepin on passive avoidance learning and the levels of tumor necrosis factor-alpha (TNF-α) in the rat hippocampus following repeated restraint stress. Male Wistar rats were divided into five groups. Chronic stress was induced by keeping animals within an adjustable restraint chamber for 6 h every day for 21 successive days. In stress-doxepin group, stressed rats were given 1, 5 and 10 mg/kg of doxepin intraperitoneally (i.p) for 21 days and before placing them in restraint chamber. Healthy animals who served as control group and stressed rats received normal saline i.p. For evaluation of learning and memory, initial latency and step-through latency were determined using passive avoidance learning test. TNF-α levels were measured in hippocampus by enzyme-linked immunosorbant assay (ELISA) at the end of experiment. Induced stress considerably decreased the step through latencies in the rats (P<0.05) but doxepin administration prevented these changes. Stress-doxepin groups did not reveal any differences compared to control group at any given doses. TNF-α level was increased significantly (P<0.05) in stress group. Only the low dose of doxepin (1 mg/kg) decreased TNF-α level. The present findings indicated that learning and memory are impaired in stressful conditions and doxepin prevented memory deficit. It seems that inflammation may involve in induced stress memory deficits, and that doxepin is helpful in alleviating the neural complications due to stress.

  10. Cell-autonomous inactivation of the Reelin pathway impairs adult neurogenesis in the hippocampus

    PubMed Central

    Teixeira, Catia M.; Kron, Michelle M.; Masachs, Nuria; Zhang, Helen; Lagace, Diane C.; Martinez, Albert; Reillo, Isabel; Duan, Xin; Bosch, Carles; Pujadas, Lluis; Brunso, Lucas; Song, Hongjun; Eisch, Amelia J.; Borrell, Victor; Howell, Brian W.; Parent, Jack M.; Soriano, Eduardo

    2012-01-01

    Adult hippocampal neurogenesis is thought to be essential for learning and memory and has been implicated in the pathogenesis of several disorders. Although recent studies have identified key factors regulating neuroprogenitor proliferation in the adult hippocampus, the mechanisms that control the migration and integration of adult-born neurons into circuits are largely unknown. Reelin is an extracellular matrix protein that is vital for neuronal development. Activation of the Reelin cascade leads to phosphorylation of disabled-1 (Dab1), an adaptor protein required for Reelin signaling. Here we used transgenic mouse and retroviral reporters along with Reelin signaling gain- and loss-of-function studies to show that the Reelin pathway regulates migration and dendritic development of adult-generated hippocampal neurons. Whereas overexpression of Reelin accelerated dendritic maturation, inactivation of the Reelin signaling pathway specifically in adult neuroprogenitor cells resulted in aberrant migration, decreased dendrite development, formation of ectopic dendrites in the hilus and the establishment of aberrant circuits. Our findings support a cell-autonomous and critical role for the Reelin pathway in regulating dendritic development and the integration of adult-generated granule cells and point to this pathway as a key regulator of adult neurogenesis. Moreover, our data reveal a novel role of the Reelin cascade in adult brain function with potential implications for the pathogenesis of several neurological and psychiatric disorders. PMID:22933789

  11. Systemic lipopolysaccharide administration impairs retrieval of context-object discrimination, but not spatial, memory: Evidence for selective disruption of specific hippocampus-dependent memory functions during acute neuroinflammation.

    PubMed

    Czerniawski, Jennifer; Miyashita, Teiko; Lewandowski, Gail; Guzowski, John F

    2015-02-01

    Neuroinflammation is implicated in impairments in neuronal function and cognition that arise with aging, trauma, and/or disease. Therefore, understanding the underlying basis of the effect of immune system activation on neural function could lead to therapies for treating cognitive decline. Although neuroinflammation is widely thought to preferentially impair hippocampus-dependent memory, data on the effects of cytokines on cognition are mixed. One possible explanation for these inconsistent results is that cytokines may disrupt specific neural processes underlying some forms of memory but not others. In an earlier study, we tested the effect of systemic administration of bacterial lipopolysaccharide (LPS) on retrieval of hippocampus-dependent context memory and neural circuit function in CA3 and CA1 (Czerniawski and Guzowski, 2014). Paralleling impairment in context discrimination memory, we observed changes in neural circuit function consistent with disrupted pattern separation function. In the current study we tested the hypothesis that acute neuroinflammation selectively disrupts memory retrieval in tasks requiring hippocampal pattern separation processes. Male Sprague-Dawley rats given LPS systemically prior to testing exhibited intact performance in tasks that do not require hippocampal pattern separation processes: novel object recognition and spatial memory in the water maze. By contrast, memory retrieval in a task thought to require hippocampal pattern separation, context-object discrimination, was strongly impaired in LPS-treated rats in the absence of any gross effects on exploratory activity or motivation. These data show that LPS administration does not impair memory retrieval in all hippocampus-dependent tasks, and support the hypothesis that acute neuroinflammation impairs context discrimination memory via disruption of pattern separation processes in hippocampus. Copyright © 2014 Elsevier Inc. All rights reserved.

  12. Systemic lipopolysaccharide administration impairs retrieval of context-object discrimination, but not spatial, memory: Evidence for selective disruption of specific hippocampus-dependent memory functions during acute neuroinflammation

    PubMed Central

    Czerniawski, Jennifer; Miyashita, Teiko; Lewandowski, Gail; Guzowski, John F.

    2014-01-01

    Neuroinflammation is implicated in impairments in neuronal function and cognition that arise with aging, trauma, and/or disease. Therefore, understanding the underlying basis of the effect of immune system activation on neural function could lead to therapies for treating cognitive decline. Although neuroinflammation is widely thought to preferentially impair hippocampus-dependent memory, data on the effects of cytokines on cognition are mixed. One possible explanation for these inconsistent results is that cytokines may disrupt specific neural processes underlying some forms of memory but not others. In an earlier study, we tested the effect of systemic administration of bacterial lipopolysaccharide (LPS) on retrieval of hippocampus-dependent context memory and neural circuit function in CA3 and CA1 (Czerniawski and Guzowski, 2014). Paralleling impairment in context discrimination memory, we observed changes in neural circuit function consistent with disrupted pattern separation function. In the current study we tested the hypothesis that acute neuroinflammation selectively disrupts memory retrieval in tasks requiring hippocampal pattern separation processes. Male Sprague-Dawley rats given LPS systemically prior to testing exhibited intact performance in tasks that do not require hippocampal pattern separation processes: novel object recognition and spatial memory in the water maze. By contrast, memory retrieval in a task thought to require hippocampal pattern separation, context-object discrimination, was strongly impaired in LPS-treated rats in the absence of any gross effects on exploratory activity or motivation. These data show that LPS administration does not impair memory retrieval in all hippocampus-dependent tasks, and support the hypothesis that acute neuroinflammation impairs context discrimination memory via disruption of pattern separation processes in hippocampus. PMID:25451612

  13. Developmental iodine deficiency and hypothyroidism impair spatial memory in adolescent rat hippocampus: involvement of CaMKII, calmodulin and calcineurin.

    PubMed

    Dong, Jing; Liu, Wanyang; Wang, Yi; Hou, Yi; Xu, Hongde; Gong, Jian; Xi, Qi; Chen, Jie

    2011-01-01

    Developmental iodine deficiency (ID) leads to inadequate thyroid hormone that impairs learning and memory with an unclear mechanism. Here, we show that hippocampal calcium/calmodulin-dependent protein kinase II (CaMKII), calmodulin and calcineurin are implicated in the impaired spatial memory in adolescent rats following developmental ID and hypothyroidism. Three developmental rat models were created by administrating dam rats with either iodine-deficient diet or propylthiouracil (PTU, 5 or 15 ppm)-added drinking water from gestational day (GD) 6 till postnatal day (PN) 28. Then, the spatial memory to a water maze test was studied in pups before PN42. After testing periods, the latency to platform and the number of error in iodine-deficient and 15 ppm PTU-treatment groups were significantly higher than those in the controls (P < 0.05). Total and phosphorylated CaMKII, calmodulin, and calcineurin in the hippocampus were detected with both the immunohistochemistry and western blotting. Without going through water maze test, iodine-deficient and 15 ppm PTU-treatment groups showed significantly lower CaMKII and calmodulin and significantly higher calcineurin than the controls in hippocampal CA1 and CA3 regions (P < 0.05). After trials of water maze task, however, CaMKII and calmodulin were up-regulated and calcineurin was down-regulated in control group (P < 0.05), but not in iodine-deficient and 15 ppm PTU-treatment groups. Data indicate that hippocampal CaMKII, calmodulin, and calcineurin are involved in the impaired spatial memory induced by developmental ID and hypothyroidism.

  14. Deletion of Tlx and social isolation impairs exercise-induced neurogenesis in the adolescent hippocampus.

    PubMed

    Kozareva, Danka A; O'Leary, Olivia F; Cryan, John F; Nolan, Yvonne M

    2017-10-03

    Adolescence is a sensitive period of neurodevelopment during which life experiences and the surrounding environment can have profound effects on the brain. Neurogenesis is a neurodevelopmental process of generating functional neurons from neural stem cells. Hippocampal neurogenesis occurs throughout the lifespan and has been shown to play a role in learning, memory and in mood regulation. In adulthood it is influenced by extrinsic environmental factors such as exercise and stress. Intrinsic factors that regulate hippocampal neurogenesis include the orphan nuclear receptor TLX (Nr2e1) which is primarily expressed in the neurogenic niches of the brain. While mechanisms regulating adult hippocampal neurogenesis have been widely studied, less is known on how hippocampal neurogenesis is affected during adolescence. Thus, the aim of this study was to investigate the influence of both TLX and isolation stress on exercise-induced increases in neurogenesis in running and sedentary conditions during adolescence. Single- (i.e. isolation stress) wild type and Nr2e1(-/-) or pair-housed wild type mice were housed in sedentary conditions or allowed free access to running wheels for 3 weeks during the adolescent period. A reduction of neuronal survival was evident in mice lacking TLX, and exercise did not increase hippocampal neurogenesis in these Nr2e1(-/-) mice. This suggests that TLX is necessary for the pro-neurogenic effects of exercise during adolescence. Interestingly, although social isolation during adolescence did not affect hippocampal neurogenesis, it prevented an exercise-induced increase in neurogenesis in the ventral hippocampus. Together these data demonstrate the importance of intrinsic and extrinsic factors in promoting an exercise-induced increase in neurogenesis at this key point in life. This article is protected by copyright. All rights reserved. © 2017 Wiley Periodicals, Inc.

  15. Piperine restores streptozotocin-induced cognitive impairments: Insights into oxidative balance in cerebrospinal fluid and hippocampus.

    PubMed

    Khalili-Fomeshi, Mohsen; Azizi, Mohammad Golparvar; Esmaeili, Mohammad Reza; Gol, Mohammad; Kazemi, Sohrab; Ashrafpour, Manouchehr; Moghadamnia, Ali Akbar; Hosseinzadeh, Soheila

    2017-09-20

    Piperine has been shown to have antioxidant activity and a cognitive-enhancing effect following long-term oral administration. In a comparative study of memantine, the current investigation threw light on the cognitive benefits of piperine. Lipid peroxidation and the ferric reducing antioxidant power (FRAP) of cerebrospinal fluid (CSF) and hippocampus in streptozotocin (STZ)-induced experimental dementia of the Alzheimer's type was measured. After reaching a criterion in a memory test, STZ-induced rats received piperine [2.5, 5, and 10mg/kg, intraperitoneally (i.p.)], vehicle, and memantine (10mg/kg, i.p.) for two weeks after the first STZ administration, or two weeks before and one week after, as a preventive approach. After the behavioral studies, samples were taken for biochemical and histological assays. An appropriate concentration of piperine (2.5mg/kg), on a daily basis, effectively increased the number of correct (non-repeated) arm entries and repressed reentry to a previously visited arm, in terms of reference errors as well as memantine (10mg/kg, i.p.), irrespective of the dose administered. The cognitive-enhancing effect induced by piperine at a relevant dose was simultaneous with CSF and hippocampal malonaldehyde decrement, and the redox balance was established to some extent by maintaining the FRAP levels of CSF near to those of the control. Similarly, the neuroprotective properties of piperine are in accordance with histopathological outcomes, which have shown an increased number of live cresyl violet (CV)-positive neurons in a dentate gyrus (DG) subregion. Therefore, the effects of piperine on the redox balance of CSF and hippocampal neurons may certainly contribute to the cognitive-enhancing activity of the drug. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Galvanic vestibular stimulation impairs cell proliferation and neurogenesis in the rat hippocampus but not spatial memory.

    PubMed

    Zheng, Yiwen; Geddes, Lisa; Sato, Go; Stiles, Lucy; Darlington, Cynthia L; Smith, Paul F

    2014-05-01

    Galvanic vestibular stimulation (GVS) is a method of activating the peripheral vestibular system using direct current that is widely employed in clinical neurological testing. Since movement is recognized to stimulate hippocampal neurogenesis and movement is impossible without activation of the vestibular system, we speculated that activating the vestibular system in rats while minimizing movement, by delivering GVS under anesthesia, would affect hippocampal cell proliferation and neurogenesis, and spatial memory. Compared with the sham control group, the number of cells incorporating the DNA replication marker, bromodeoxyuridine (BrdU), was significantly reduced in the bilateral hippocampi in both the cathode left-anode right and cathode right-anode left stimulation groups (P ≤ 0.0001). The majority of the BrdU(+ve) cells co-expressed Ki-67, a marker for the S phase of the cell cycle, suggesting that these BrdU(+ve) cells were still in the cell cycle; however, there was no significant difference in the degree of co-labeling between the two stimulation groups. Single labeling for doublecortin (DCX), a marker of immature neurons, showed that while there was no significant difference between the different groups in the number of DCX(+ve) cells in the right dentate gryus, in the left dentate gyrus there was a significant decrease in the cathode left-anode right group compared with the sham controls (P ≤ 0.03). Nonetheless, when animals were tested in place recognition, object exploration and Morris water maze tasks, there were no significant differences between the GVS groups and the sham controls. These results suggest that GVS can have striking effects on cell proliferation and possibly neurogenesis in the hippocampus, without affecting spatial memory. Copyright © 2014 Wiley Periodicals, Inc.

  17. Fragmentation of Rapid Eye Movement and Nonrapid Eye Movement Sleep without Total Sleep Loss Impairs Hippocampus-Dependent Fear Memory Consolidation

    PubMed Central

    Lee, Michael L.; Katsuyama, Ângela M.; Duge, Leanne S.; Sriram, Chaitra; Krushelnytskyy, Mykhaylo; Kim, Jeansok J.; de la Iglesia, Horacio O.

    2016-01-01

    Study Objectives: Sleep is important for consolidation of hippocampus-dependent memories. It is hypothesized that the temporal sequence of nonrapid eye movement (NREM) sleep and rapid eye movement (REM) sleep is critical for the weakening of nonadaptive memories and the subsequent transfer of memories temporarily stored in the hippocampus to more permanent memories in the neocortex. A great body of evidence supporting this hypothesis relies on behavioral, pharmacological, neural, and/or genetic manipulations that induce sleep deprivation or stage-specific sleep deprivation. Methods: We exploit an experimental model of circadian desynchrony in which intact animals are not deprived of any sleep stage but show fragmentation of REM and NREM sleep within nonfragmented sleep bouts. We test the hypothesis that the shortening of NREM and REM sleep durations post-training will impair memory consolidation irrespective of total sleep duration. Results: When circadian-desynchronized animals are trained in a hippocampus-dependent contextual fear-conditioning task they show normal short-term memory but impaired long-term memory consolidation. This impairment in memory consolidation is positively associated with the post-training fragmentation of REM and NREM sleep but is not significantly associated with the fragmentation of total sleep or the total amount of delta activity. We also show that the sleep stage fragmentation resulting from circadian desynchrony has no effect on hippocampus-dependent spatial memory and no effect on hippocampus-independent cued fear-conditioning memory. Conclusions: Our findings in an intact animal model, in which sleep deprivation is not a confounding factor, support the hypothesis that the stereotypic sequence and duration of sleep stages play a specific role in long-term hippocampus-dependent fear memory consolidation. Citation: Lee ML, Katsuyama AM, Duge LS, Sriram C, Krushelnytskyy M, Kim JJ, de la Iglesia HO. Fragmentation of rapid eye movement

  18. Ketogenic diet does not impair spatial ability controlled by the hippocampus in male rats.

    PubMed

    Fukushima, Atsushi; Ogura, Yuji; Furuta, Miyako; Kakehashi, Chiaki; Funabashi, Toshiya; Akema, Tatsuo

    2015-10-05

    A ketogenic diet was recently shown to reduce glutamate accumulation in synaptic vesicles, decreasing glutamate transmission. We questioned whether a ketogenic diet affects hippocampal function, as glutamate transmission is critically involved in visuospatial ability. In the present study, male Wistar rats were maintained on a ketogenic diet containing 10% protein and 90% fat with complements for 3 weeks to change their energy expenditure from glucose-dependent to fat-dependent. Control rats were fed a diet containing 10% protein, 10% fat, and 80% carbohydrates. The fat-dependent energy expenditure induced by the ketogenic diet led to decreased body weight and increased blood ketone production, though the rats in the two groups consumed the same number of calories. The ketogenic diet did not alter food preferences for the control or high-fat diet containing 10% protein, 45% fat, and 45% carbohydrates. Anxiety in the open field was not altered by ingestion the ketogenic diet. However, rats fed the ketogenic diet performed better in the Y-maze test than rats fed the control diet. No difference was observed between the two groups in the Morris water maze test. Finally, Western blot revealed that the hippocampal expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptor subunit 1 (GluR1) was significantly increased in mice fed a ketogenic diet. These results suggest that hippocampal function is not impaired by a ketogenic diet and we speculate that the fat-dependent energy expenditure does not impair visuospatial ability.

  19. Zaprinast impairs spatial memory by increasing PDE5 expression in the rat hippocampus.

    PubMed

    Giorgi, Mauro; Pompili, Assunta; Cardarelli, Silvia; Castelli, Valentina; Biagioni, Stefano; Sancesario, Giuseppe; Gasbarri, Antonella

    2015-02-01

    In this work, we report the effect of post-training intraperitoneal administration of zaprinast on rat memory retention in the Morris water maze task that revealed a significant memory impairment at the intermediate dose of 10mg/kg. Zaprinast is capable of inhibiting both striatal and hippocampal PDE activity but to a different extent which is probably due to the different PDE isoforms expressed in these areas. To assess the possible involvement of cyclic nucleotides in rat memory impairment, we compared the effects obtained 30 min after the zaprinast injection with respect to 24h after injection by measuring both cyclic nucleotide levels and PDE activity. As expected, 30 min after the zaprinast administration, we observed an increase of cyclic nucleotides, which returned to a basal level within 24h, with the exception of the hippocampal cGMP which was significantly decreased at the dose of 10mg/kg of zaprinast. This increase in the hippocampal region is the result of a cGMP-specific PDE5 induction, confirmed by sildenafil inhibition, in agreement with literature data that demonstrate transcriptional regulation of PDE5 by cAMP/cGMP intracellular levels. Our results highlight the possible rebound effect of PDE inhibitors.

  20. The unique alterations of hippocampus and cognitive impairment in chronic obstructive pulmonary disease

    PubMed Central

    2013-01-01

    Background Cognitive impairment has been found in chronic obstructive pulmonary disease (COPD) patients. However, the structural alteration of the brain and underlying mechanisms are poorly understood. Methods Thirty-seven mild-to-moderate COPD patients, forty-eight severe COPD patients, and thirty-one control subjects were recruited for cognitive test and neuroimaging studies. Serum levels of S100B,pulmonary function and arterial blood gas levels were also evaluated in each subject. Results The hippocampal volume was significantly smaller in COPD patients compared to the control group. It is positively correlated with a mini mental state examination (MMSE) score, SaO2 in mild-to-moderate COPD patients, the levels of PaO2 in both mild-to-moderate and severe COPD patients. Higher S100B concentrations were observed in mild-to-moderate COPD patients, while the highest S100B level was found in severe COPD patients when compared to the control subjects. S100B levels are negatively associated with MMSE in both mild-to-moderate and severe COPD patients and also negatively associated with the hippocampal volume in the total COPD patients. Conclusions Hippocampal atrophy based on quantitative assessment by magnetic resonance imaging does occur in COPD patients, which may be associated with cognitive dysfunction and the most prevalent mechanism accountable for hippocampal atrophy is chronic hypoxemia in COPD. Higher serum S100B levels may be peripheral biochemical marker for cognitive impairment in COPD. PMID:24359080

  1. Decreased AMPA GluR2, but not GluR3, mRNA expression in rat amygdala and dorsal hippocampus following morphine-induced behavioural sensitization.

    PubMed

    Sepehrizadeh, Zargham; Bahrololoumi Shapourabadi, Mina; Ahmadi, Shamseddin; Hashemi Bozchlou, Saeed; Zarrindast, Mohammad-Reza; Sahebgharani, Mousa

    2008-11-01

    1. Repeated administration of psychostimulants and micro-opioid receptor agonists elicits a progressive enhancement of drug-induced behavioural responses, a phenomenon termed behavioural sensitization. These changes in behaviour may reflect plastic changes requiring regulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) receptor function. 2. In the present study, rats were treated for 7 days with saline or morphine (10 mg/kg). After a washout period of either 24 h or 7 days, locomotion, oral stereotypy and state-dependent memory in a passive avoidance test were measured in the presence or absence of 6-cyano-7-nitroquinoxaline-2,3-dione disodium salt (CNQX; 3 mg/kg), an AMPA receptor antagonist. In order to evaluate the mechanism underlying the behavioural responses, quantitative real-time reverse transcription-polymerase chain reaction was used to evaluate mRNA expression of the AMPA receptor subunits GluR2 and GluR3 in the striatum, prefrontal cortex, hippocampus, hypothalamus and amygdala of animals treated repeatedly with morphine. 3. The results indicate that repeated morphine treatment followed by 7 days (but not 24 h) washout produces behavioural sensitization, as determined by locomotion, oral stereotypy and state-dependent memory. Blockade of AMPA receptors with CNQX on the test day did not alter these behavioural responses. In addition, repeated morphine treatment followed by 7 days (but not 24 h) washout decreased GluR2 mRNA expression in both the amygdala (by 50%) and hippocampus (by 35%). Repeated morphine treatment did not alter GluR3 mRNA expression in any brain area assessed. 4. These data imply that AMPA receptors are involved in the development (but not expression) phase of behavioural sensitization. The decreases in GluR2 mRNA expression in the amygdala and hippocampus may result in the formation of calcium-permeable AMPA receptors, which are believed to play an important role in behavioural sensitization.

  2. Associative learning over trials activates the hippocampus in healthy elderly but not mild cognitive impairment.

    PubMed

    Johnson, Sterling C; Schmitz, Taylor W; Asthana, Sanjay; Gluck, Mark A; Myers, Catherine

    2008-03-01

    The ability to form associations between choice alternatives and their contingent outcomes is an important aspect of learning that may be sensitive to hippocampal dysfunction in memory disorders of aging such as amnestic mild cognitive impairment (MCIa), or early Alzheimer disease. In this preliminary study we examined brain activation using functional magnetic resonance imaging (fMRI) in 12 healthy elderly participants and nine patients with MCIa during an associative learning task. Using a high-field 3.0-Tesla MRI scanner, we examined the dynamic neural response during associative learning over trials. The slope of signal attenuation associated with learning was analyzed for differences between groups within an a priori defined hippocampal region. Results indicated dynamic signal attenuation associated with learning in the healthy elderly sample, but not in MCIa. The absence of an associative learning effect in the MCIa sample reaffirms an important link between the learning difficulties that are commonly encountered in MCIa and the mesial temporal region.

  3. Osmotin attenuates amyloid beta-induced memory impairment, tau phosphorylation and neurodegeneration in the mouse hippocampus

    PubMed Central

    Ali, Tahir; Yoon, Gwang Ho; Shah, Shahid Ali; Lee, Hae Young; Kim, Myeong Ok

    2015-01-01

    The pathological hallmarks of Alzheimer’s disease (AD) include amyloid beta (Aβ) accumulation, neurofibrillary tangle formation, synaptic dysfunction and neuronal loss. In this study, we investigated the neuroprotection of novel osmotin, a plant protein extracted from Nicotiana tabacum that has been considered to be a homolog of mammalian adiponectin. Here, we observed that treatment with osmotin (15 μg/g, intraperitoneally, 4 hr) at 3 and 40 days post-intracerebroventricular injection of Aβ1-42 significantly ameliorated Aβ1-42-induced memory impairment in mice. These results revealed that osmotin reverses Aβ1-42 injection-induced synaptic deficits, Aβ accumulation and BACE-1 expression. Treatment with osmotin also alleviated the Aβ1-42-induced hyperphosphorylation of the tau protein at serine 413 through the regulation of the aberrant phosphorylation of p-PI3K, p-Akt (serine 473) and p-GSK3β (serine 9). Moreover, our western blots and immunohistochemical results indicated that osmotin prevented Aβ1-42-induced apoptosis and neurodegeneration in the Aβ1-42-treated mice. Furthermore, osmotin attenuated Aβ1-42-induced neurotoxicity in vitro. To our knowledge, this study is the first to investigate the neuroprotective effect of a novel osmotin against Aβ1-42-induced neurotoxicity. Our results demonstrated that this ubiquitous plant protein could potentially serve as a novel, promising, and accessible neuroprotective agent against progressive neurodegenerative diseases such as AD. PMID:26118757

  4. Dopamine D1 receptor blockade impairs alcohol seeking without reducing dorsal striatal activation to cues of alcohol availability

    PubMed Central

    Fanelli, Rebecca R; Robinson, Donita L

    2015-01-01

    Introduction Alcohol-associated cues activate both ventral and dorsal striatum in functional brain imaging studies of heavy drinkers. In rodents, alcohol-associated cues induce changes in neuronal firing frequencies and increase dopamine release in ventral striatum, but the impact of alcohol-associated cues on neuronal activity in dorsal striatum is unclear. We previously reported phasic changes in action potential frequency in the dorsomedial and dorsolateral striatum after cues that signaled alcohol availability, prompting approach behavior. Methods We investigated the hypothesis that dopamine transmission modulates these phasic firing changes. Rats were trained to self-administer alcohol, and neuronal activity was monitored with extracellular electrophysiology during “anticipatory” cues that signaled the start of the operant session. Sessions were preceded by systemic administration of the D1-type dopamine receptor antagonist SCH23390 (0, 10, and 20 μg/kg). Results SCH23390 significantly decreased firing rates during the 60 s prior to cue onset without reducing phasic excitations immediately following the cues. While neuronal activation to cues might be expected to initiate behavioral responses, in this study alcohol seeking was reduced despite the presence of dorsal striatal excitations to alcohol cues. Conclusions These data suggest that D1 receptor antagonism reduces basal firing rates in the dorsal striatum and modulates the ability of neuronal activation to “anticipatory” cues to initiate alcohol seeking in rats with an extensive history of alcohol self-administration. PMID:25642390

  5. Dopamine D1 receptor blockade impairs alcohol seeking without reducing dorsal striatal activation to cues of alcohol availability.

    PubMed

    Fanelli, Rebecca R; Robinson, Donita L

    2015-02-01

    Alcohol-associated cues activate both ventral and dorsal striatum in functional brain imaging studies of heavy drinkers. In rodents, alcohol-associated cues induce changes in neuronal firing frequencies and increase dopamine release in ventral striatum, but the impact of alcohol-associated cues on neuronal activity in dorsal striatum is unclear. We previously reported phasic changes in action potential frequency in the dorsomedial and dorsolateral striatum after cues that signaled alcohol availability, prompting approach behavior. We investigated the hypothesis that dopamine transmission modulates these phasic firing changes. Rats were trained to self-administer alcohol, and neuronal activity was monitored with extracellular electrophysiology during "anticipatory" cues that signaled the start of the operant session. Sessions were preceded by systemic administration of the D1-type dopamine receptor antagonist SCH23390 (0, 10, and 20 μg/kg). SCH23390 significantly decreased firing rates during the 60 s prior to cue onset without reducing phasic excitations immediately following the cues. While neuronal activation to cues might be expected to initiate behavioral responses, in this study alcohol seeking was reduced despite the presence of dorsal striatal excitations to alcohol cues. These data suggest that D1 receptor antagonism reduces basal firing rates in the dorsal striatum and modulates the ability of neuronal activation to "anticipatory" cues to initiate alcohol seeking in rats with an extensive history of alcohol self-administration.

  6. Date seed extract ameliorates β-amyloid-induced impairments in hippocampus of male rats.

    PubMed

    Dehghanian, Farzaneh; Kalantaripour, Taj Pari; Esmaeilpour, Khadijeh; Elyasi, Leila; Oloumi, Hakime; Pour, Fatmeh Mehdi; Asadi-Shekaari, Majid

    2017-05-01

    Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder among the elderly. Because the existing treatments for Alzheimer's disease only offer limited symptomatic alleviation, more efficient therapeutic agents are urgently needed. Date seed is a hepatoprotective and neuroprotective agent. Date seed extract (DSE) has bioactive components like phenolics, flavonoids, and vitamins. In view of the ameliorative effects of DSE against an oxidative injury, the current study was designed to reveal whether DSE has a neuroprotective resource in the rat model of Alzheimer's disease. In the current study, 24 adult male Sprague-Dawely rats were divided into three groups (n=8) of: Sham (Distilled Water, 3μl intracerebroventricular (ICV) injection), β-Amyloid (β-amyloid, 3μl ICV injection), and DSE-treated groups (80mg/kg, Intraperitoneal (IP) injection), for 12days. Twelve days after Alzheimer induction, behavioral analysis, the Morris Water Maze (MWM), as well as western blot and histological studies were performed to reveal the neuroprotective potential of DSE in rats. Administration of DSE significantly restored memory and learning impairments induced by Aβ in the MWM test. DSE significantly decreased the caspase-3 expression level in the treated group. In addition, DSE reduced the number of degenerated neurons in the hippocampal CA1 subfield of the DSE treated rats. These results demonstrate that DSE may have beneficial effects in the prevention of Aβ-induced Alzheimer in a rat model. Date seed extract may have advantageous effects in preventing Alzheimer's disease in male rats. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  7. Optogenetic activation of intracellular adenosine A2A receptor signaling in the hippocampus is sufficient to trigger CREB phosphorylation and impair memory.

    PubMed

    Li, P; Rial, D; Canas, P M; Yoo, J-H; Li, W; Zhou, X; Wang, Y; van Westen, G J P; Payen, M-P; Augusto, E; Gonçalves, N; Tomé, A R; Li, Z; Wu, Z; Hou, X; Zhou, Y; IJzerman, A P; PIJzerman, Ad; Boyden, E S; Cunha, R A; Qu, J; Chen, J-F

    2015-11-01

    Human and animal studies have converged to suggest that caffeine consumption prevents memory deficits in aging and Alzheimer's disease through the antagonism of adenosine A2A receptors (A2ARs). To test if A2AR activation in the hippocampus is actually sufficient to impair memory function and to begin elucidating the intracellular pathways operated by A2AR, we have developed a chimeric rhodopsin-A2AR protein (optoA2AR), which retains the extracellular and transmembrane domains of rhodopsin (conferring light responsiveness and eliminating adenosine-binding pockets) fused to the intracellular loop of A2AR to confer specific A2AR signaling. The specificity of the optoA2AR signaling was confirmed by light-induced selective enhancement of cAMP and phospho-mitogen-activated protein kinase (p-MAPK) (but not cGMP) levels in human embryonic kidney 293 (HEK293) cells, which was abolished by a point mutation at the C terminal of A2AR. Supporting its physiological relevance, optoA2AR activation and the A2AR agonist CGS21680 produced similar activation of cAMP and p-MAPK signaling in HEK293 cells, of p-MAPK in the nucleus accumbens and of c-Fos/phosphorylated-CREB (p-CREB) in the hippocampus, and similarly enhanced long-term potentiation in the hippocampus. Remarkably, optoA2AR activation triggered a preferential p-CREB signaling in the hippocampus and impaired spatial memory performance, while optoA2AR activation in the nucleus accumbens triggered MAPK signaling and modulated locomotor activity. This shows that the recruitment of intracellular A2AR signaling in the hippocampus is sufficient to trigger memory dysfunction. Furthermore, the demonstration that the biased A2AR signaling and functions depend on intracellular A2AR loops prompts the possibility of targeting the intracellular A2AR-interacting partners to selectively control different neuropsychiatric behaviors.

  8. Bupropion-induced inhibition of α7 nicotinic acetylcholine receptors expressed in heterologous cells and neurons from dorsal raphe nucleus and hippocampus.

    PubMed

    Vázquez-Gómez, Elizabeth; Arias, Hugo R; Feuerbach, Dominik; Miranda-Morales, Marcela; Mihailescu, Stefan; Targowska-Duda, Katarzyna M; Jozwiak, Krzysztof; García-Colunga, Jesús

    2014-10-05

    The pharmacological activity of bupropion was compared between α7 nicotinic acetylcholine receptors expressed in heterologous cells and hippocampal and dorsal raphe nucleus neurons. The inhibitory activity of bupropion was studied on GH3-α7 cells by Ca2+ influx, as well as on neurons from the dorsal raphe nucleus and interneurons from the stratum radiatum of the hippocampal CA1 region by using a whole-cell voltage-clamp technique. In addition, the interaction of bupropion with the α7 nicotinic acetylcholine receptor was determined by [3H]imipramine competition binding assays and molecular docking. The fast component of acetylcholine- and choline-induced currents from both brain regions was inhibited by methyllycaconitine, indicating the participation of α7-containing nicotinic acetylcholine receptors. Choline-induced currents in hippocampal interneurons were partially inhibited by 10 µM bupropion, a concentration that could be reached in the brain during clinical administration. Additionally, both agonist-induced currents were reversibly inhibited by bupropion at concentrations that coincide with its inhibitory potency (IC50=54 µM) and binding affinity (Ki=63 µM) for α7 nicotinic acetylcholine receptors from heterologous cells. The [3H]imipramine competition binding and molecular docking results support a luminal location for the bupropion binding site(s). This study may help to understand the mechanisms of actions of bupropion at neuronal and molecular levels related with its therapeutic actions on depression and for smoking cessation. Copyright © 2014 Elsevier B.V. All rights reserved.

  9. Allele-specific differences in activity of a novel cannabinoid receptor 1 (CNR1) gene intronic enhancer in hypothalamus, dorsal root ganglia, and hippocampus.

    PubMed

    Nicoll, Gemma; Davidson, Scott; Shanley, Lynne; Hing, Ben; Lear, Marissa; McGuffin, Peter; Ross, Ruth; MacKenzie, Alasdair

    2012-04-13

    Polymorphisms within intron 2 of the CNR1 gene, which encodes cannabinoid receptor 1 (CB(1)), have been associated with addiction, obesity, and brain volume deficits. We used comparative genomics to identify a polymorphic (rs9444584-C/T) sequence (ECR1) in intron 2 of the CNR1 gene that had been conserved for 310 million years. The C-allele of ECR1 (ECR1(C)) acted as an enhancer in hypothalamic and dorsal root ganglia cells and responded to MAPK activation through the MEKK pathway but not in hippocampal cells. However, ECR1(T) was significantly more active in hypothalamic and dorsal root ganglia cells but, significantly, and in contrast to ECR1(C), was highly active in hippocampal cells where it also responded strongly to activation of MAPK. Intriguingly, rs9444584 is in strong linkage disequilibrium with two other SNPs (rs9450898 (r(2) = 0.841) and rs2023239 (r(2) = 0.920)) that have been associated with addiction, obesity (rs2023239), and reduced fronto-temporal white matter volumes in schizophrenia patients as a result of cannabis misuse (rs9450898). Considering their high linkage disequilibrium and the increased response of ECR1(T) to MAPK signaling when compared with ECR1(C), it is possible that the functional effects of the different alleles of rs9444584 may play a role in the conditions associated with rs9450898 and rs2023239. Further analysis of the different alleles of ECR1 may lead to a greater understanding of the role of CNR1 gene misregulation in these conditions as well as chronic inflammatory pain.

  10. Traumatic Brain Injury Impairs Soluble N-Ethylmaleimide-Sensitive Factor Attachment Protein Receptor Complex Formation and Alters Synaptic Vesicle Distribution in the Hippocampus

    PubMed Central

    Carlson, Shaun W.; Yan, Hong; Ma, Michelle; Li, Youming; Henchir, Jeremy

    2016-01-01

    Abstract Traumatic brain injury (TBI) impairs neuronal function and can culminate in lasting cognitive impairment. While impaired neurotransmitter release has been well established after experimental TBI, little is understood about the mechanisms underlying this consequence. In the synapse, vesicular docking and neurotransmitter release requires the formation of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex. Impairments in vesicle docking, and alterations in SNARE complex formation are associated with impaired neurotransmitter release. We hypothesized that TBI reduces SNARE complex formation and disrupts synaptic vesicle distribution in the hippocampus. To examine the effect of TBI on the SNARE complex, rats were subjected to controlled cortical impact (CCI) or sham injury, and the brains were assessed at 6 h, 1 d, one week, two weeks, or four weeks post-injury. Immunoblotting of hippocampal homogenates revealed significantly reduced SNARE complex formation at one week and two weeks post-injury. To assess synaptic vesicles distribution, rats received CCI or sham injury and the brains were processed for transmission electron microscopy at one week post-injury. Synapses in the hippocampus were imaged at 100k magnification, and vesicle distribution was assessed in pre-synaptic terminals at the active zone. CCI resulted in a significant reduction in vesicle number within 150 nm of the active zone. These findings provide the first evidence of TBI-induced impairments in synaptic vesicle docking, and suggest that reductions in the pool of readily releasable vesicles and impaired SNARE complex formation are two novel mechanisms contributing to impaired neurotransmission after TBI. PMID:25923735

  11. Proteolysis of calcineurin is increased in human hippocampus during mild cognitive impairment and is stimulated by oligomeric Abeta

    PubMed Central

    Abdul, Hafiz Mohmmad; Baig, Irfan; LeVine, Harry; Guttmann, Rodney P; Norris, Christopher M.

    2011-01-01

    Summary Recent reports demonstrate that the activation and interaction of the protease calpain (CP) and the protein phosphatase calcineurin (CN) are elevated in the late stages of Alzheimer’s disease (AD). However, the extent to which CPs and CN interact during earlier stages of disease progression remains unknown. Here, we investigated CP and CN protein levels in cytosolic, nuclear, and membrane fractions prepared from human postmortem hippocampal tissue from aged non-demented subjects, and subjects diagnosed with mild cognitive impairment (MCI). The results revealed a parallel increase in CP I and the 48 kDa CN-Aα (ΔCN-Aα48) proteolytic fragment in cytosolic fractions during MCI. In primary rat hippocampal cultures, CP-dependent proteolysis and activation of CN was stimulated by application of oligomeric Aβ(1-42) peptides. Deleterious effects of Aβ on neuronal morphology were reduced by blockade of either CP or CN. NMDA-type glutamate receptors, which help regulate cognition and neuronal viability, and are modulated by CPs and CN, were also investigated in human hippocampus. Relative to controls, MCI subjects showed significantly greater proteolytic levels of the NR2B subunit. Within subjects, the extent of NR2B proteolysis was strongly correlated with the generation of ΔCN-Aα48 in the cytosol. A similar proteolytic pattern for NR2B was also observed in primary rat hippocampal cultures treated with oligomeric Aβ and prevented by inhibition of CP or CN. Together, the results demonstrate that the activation and interaction of CPs and CN are increased early in cognitive decline associated with AD and may help drive other pathologic processes during disease progression. PMID:20969723

  12. NMDA receptor subunit and CaMKII changes in rat hippocampus by congenital HCMV infection: a mechanism for learning and memory impairment.

    PubMed

    Wu, De; Yang, Li; Bu, Xiaosong; Tang, Jiulai; Fan, Xiaocheng

    2017-03-22

    The aim of this study was to investigate the effects of congenital human cytomegalovirus infection on the expression levels of N-methyl-D-aspartate receptors (NRs) and Ca/calmodulin-dependent protein kinase II (CaMKII) in the hippocampal neurons of neonatal Sprague-Dawley (SD) rats. Pregnant SD rats were divided into an experimental group and a control group (n=10 in each group). Spatial learning and memory of the offspring of SD rats were evaluated using the Morris water-maze test. Pathological studies of hippocampus sections were carried out. The concentration of [Ca] was measured using a dual-wavelength spectrophotometer method. The expression levels of NRs were detected by an immunohistochemical study. Western blot was performed to detect the expression level of CaMKII. In the Morris water-maze test, the rats in the experimental group showed significantly increased escape latency and distance traveled than the control group. Damaged and structural disorders of the dentate granule in the hippocampus were found in the experimental rats. Immunohistochemistry results showed that the expression levels of NR subunits in the hippocampus of the experimental group were significantly decreased. The concentration of [Ca] in the experimental group was significantly increased. In contrast, the level of CaMKII in the experimental group was significantly decreased. The expressions of the NR subunit and CaMKII were decreased in rat hippocampus by human cytomegalovirus congenital infection, which may be associated with the mechanism underlying the impairment of learning and memory function.

  13. Dexmedetomidine alleviates cerebral ischemia-induced short-term memory impairment by inhibiting the expression of apoptosis-related molecules in the hippocampus of gerbils

    PubMed Central

    Choi, In-Young; Hwang, Lakkyong; Jin, Jun-Jang; Ko, Il-Gyu; Kim, Sung-Eun; Shin, Mal-Soon; Shin, Key-Moon; Kim, Chang-Ju; Park, Sung-Wook; Han, Jin-Hee; Yi, Jae-Woo

    2017-01-01

    Cerebral ischemia results from cerebrovascular occlusion, which leads to neuronal cell death and eventually causes neurological impairments. Dexmedetomidine is a potent and highly selective α2-adrenoreceptor agonist with actions such as sedation, anxiolysis, analgesia and anesthetic-sparing effects. We investigated the effect of dexmedetomidine on apoptosis in the hippocampus after transient global ischemia in gerbils. Transient global ischemia was induced by ligation of both common carotid arteries. Dexmedetomidine was administrated intraperitoneally at three respective doses (0.1, 1 and 10 µg/kg) once per day for 14 consecutive days beginning a day after surgery. Short-term memory was assessed by use of a step-down avoidance task. Apoptosis was evaluated by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling assay, immunohistochemistry for caspase-3, and western blot analysis of Bcl-2-associated X protein, B-cell lymphoma 2, Bid, cytochrome c, apoptotic protease activating factor-1 and caspase-9 in the hippocampus. Induction of global ischemia deteriorated short-term memory by enhancing the expression of apoptosis-related molecules in the hippocampus. Treatment with dexmedetomidine suppressed the expression of apoptosis-related molecules under ischemic conditions, resulting in short-term memory improvement. Under normal conditions, dexmedetomidine exerted no significant effect on apoptosis in the hippocampus. The present results suggest that the α2-adrenoceptor agonist dexmedetomidine may be a useful therapeutic agent for the treatment of ischemic brain diseases. PMID:28123477

  14. drd2-cre:ribotag mouse line unravels the possible diversity of dopamine d2 receptor-expressing cells of the dorsal mouse hippocampus.

    PubMed

    Puighermanal, Emma; Biever, Anne; Espallergues, Julie; Gangarossa, Giuseppe; De Bundel, Dimitri; Valjent, Emmanuel

    2015-07-01

    Increasing evidences suggest that dopamine facilitates the encoding of novel memories by the hippocampus. However, the role of dopamine D2 receptors (D2R) in such regulations remains elusive due to the lack of the precise identification of hippocampal D2R-expressing cells. To address this issue, mice expressing the ribosomal protein Rpl22 tagged with the hemagglutinin (HA) epitope were crossed with Drd2-Cre mice allowing the selective expression of HA in D2R-containing cells (Drd2-Cre:RiboTag mice). This new transgenic model revealed a more widespread pattern of D2R-expressing cells identified by HA immunoreactivity than the one initially reported in Drd2-EGFP mice, in which the hilar mossy cells were the main neuronal population detectable. In Drd2-Cre:RiboTag mice, scattered HA/GAD67-positive neurons were detected throughout the CA1/CA3 subfields, being preferentially localized in stratum oriens and stratum lacunosum-moleculare. At the cellular level, HA-labeled cells located in CA1/CA3 subfields co-localized with calcium-binding proteins (parvalbumin, calbindin, and calretinin), neuropeptides (neuropeptide Y, somatostatin), and other markers (neuronal nitric oxide synthase, mGluR1α, reelin, coupTFII, and potassium channel-interacting protein 1). These results suggest that in addition to the glutamatergic hilar mossy cells, D2R-expressing cells constitute a subpopulation of GABAergic hippocampal interneurons. © 2014 Wiley Periodicals, Inc.

  15. Differential Regulation of MAPK Phosphorylation in the Dorsal Hippocampus in Response to Prolonged Morphine Withdrawal-Induced Depressive-Like Symptoms in Mice

    PubMed Central

    Shi, Jianguo; Wu, Bin; Dang, Wei; Du, Ying; Zhou, Qiong; Wang, Jianhua; Zhang, Rui

    2013-01-01

    Depression is one of the most frequent neuropsychiatric comorbidities associated with opiate addiction. Mitogen activated protein kinase (MAPK) and MAPK phosphatase (MKP) are involved in drug addiction and depression. However, the potential role of MAPK and MKP in depression caused by morphine withdrawal remains unclear. We utilized a mouse model of repeated morphine administration to examine the molecular mechanisms that contribute to prolonged withdrawal induced depressive-like behaviors. Depressive-like behaviors were significant at 1 week after withdrawal and worsened over time. Phospho-ERK (extracellular signal-regulated protein kinase) was decreased and MKP-1 was elevated in the hippocampus, and JNK (c-Jun N-terminal protein kinase), p38 (p38 protein kinase) and MKP-3 were unaffected. A pharmacological blockade of MKP-1 by intra-hippocampal sanguinarine (SA) infusion prevented the development of depressive-like behaviors and resulted in relatively normal levels of MKP-1 and phospho-ERK after withdrawal. Our findings support the association between hippocampal MAPK phosphorylation and prolonged morphine withdrawal-induced depression, and emphasize the MKP-1 as an negative regulator of the ERK phosphorylation that contributes to depression. PMID:23823128

  16. Rapid effects of the G-protein coupled oestrogen receptor (GPER) on learning and dorsal hippocampus dendritic spines in female mice.

    PubMed

    Gabor, Christopher; Lymer, Jennifer; Phan, Anna; Choleris, Elena

    2015-10-01

    Recently, oestrogen receptors (ERs) have been implicated in rapid learning processes. We have previously shown that 17β-estradiol, ERα and ERβ agonists can improve learning within 40 min of drug administration in mice. However, oestrogen action at the classical receptors may only in part explain these rapid learning effects. Chronic treatment of a G-protein coupled oestrogen receptor (GPER) agonist has been shown to affect learning and memory in ovariectomized rats, yet little is known about its rapid learning effects. Therefore we investigated whether the GPER agonist G-1 at 1 μg/kg, 6 μg/kg, 10 μg/kg, and 30 μg/kg could affect social recognition, object recognition, and object placement learning in ovariectomized CD1 mice within 40 min of drug administration. We also examined rapid effects of G-1 on CA1 hippocampal dendritic spine density and length within 40 min of drug administration, but in the absence of any learning tests. Results suggest a rapid enhancing effect of GPER activation on social recognition, object recognition and object placement learning. G-1 treatment also resulted in increased dendritic spine density in the stratum radiatum of the CA1 hippocampus. Hence GPER, along with the classical ERs, may mediate the rapid effects of oestrogen on learning and neuronal plasticity. To our knowledge, this is the first report of GPER effects occurring within a 40 min time frame.

  17. Short-Term Ketamine Treatment Decreases Oxidative Stress Without Influencing TRPM2 and TRPV1 Channel Gating in the Hippocampus and Dorsal Root Ganglion of Rats.

    PubMed

    Demirdaş, Arif; Nazıroğlu, Mustafa; Övey, Ishak Suat

    2017-01-01

    Calcium ions (Ca(2+)) are important second messengers in neurons. Ketamine (KETAM) is an anesthetic and analgesic, with psychotomimetic effects and abuse potential. KETAM modulates the entry of Ca(2+) in neurons through glutamate receptors, but its effect on transient receptor potential melastatin 2 (TRPM2) and transient receptor potential vanilloid 1 (TRPV1) channels has not been clarified. This study investigated the short-term effects of KETAM on oxidative stress and TRPM2 and TRPV1 channel gating in hippocampal and dorsal root ganglion (DRG) neurons of rats. Freshly isolated hippocampal and DRG neurons were incubated for 24 h with KETAM (0.3 mM). The TRPM2 channel antagonist, N-(p-amylcinnamoyl)anthranilic acid (ACA), inhibited cumene hydroperoxide and ADP-ribose-induced TRPM2 currents in the neurons, and capsazepine (CPZ) inhibited capsaicin-induced TRPV1 currents. The TRPM2 and TRPV1 channel current densities and intracellular free calcium ion concentration of the neurons were lower in the neurons exposed to ACA and CPZ compared to the control neurons, respectively. However, the values were not further decreased by the KETAM + CPZ and KETAM + ACA treatments. KETAM decreased lipid peroxidation levels in the neurons but increased glutathione peroxidase activity. In conclusion, short-term KETAM treatment decreased oxidative stress levels but did not seem to influence TRPM2- and TRPV1-mediated Ca(2+) entry.

  18. Effects of electroacupuncture on ethanol-induced impairments of spatial learning and memory and Fos expression in the hippocampus in rats.

    PubMed

    Lu, Bin; Ma, Zhao; Cheng, Fei; Zhao, Yan; Zhang, Xin; Mao, Huijuan; Shen, Xueyong; Liu, Sheng

    2014-07-25

    It is well established that alcohol impairs spatial learning and memory. Here, we investigated the effects of electroacupuncture (EA) at ST36 or nonacupoint on ethanol-induced learning and memory impairment and the expression of Fos in the hippocampus. Ethanol (5g/kg) was administered intragastrically once a day for 5 consecutive days; 2Hz EA was administered immediately after ethanol exposure. After a 2-day ethanol abstinence, for 6 consecutive days, the rats were submitted to Morris water maze training. Probe trials were performed on 1 day after the final training session. We also applied immunohistochemistry to detect Fos-positive nuclei in the hippocampus. We found that 5-day ethanol exposure markedly decreased spatial learning and memory abilities in the Morris water maze task as indicated by escape latency and time in the target quadrant. EA treatment shortened the time of reaching platform and increased times traveled in the target quadrant (P<0.05). Animals administered with ethanol emitted significantly fewer Fos expression in the hippocampal CA1 area. EA increased Fos expression in the hippocampal CA1 area. Significant correlations were obtained between Fos protein expression in CA1 and time in the target quadrant. Altogether, these results suggest that EA protects against ethanol-induced impairments of spatial learning and memory, which may be involved in the hippocampal CA1 area. EA treatment may provide a novel nonpharmacological strategy for ethanol-induced learning and memory impairment.

  19. Dorsal hippocampal NMDA receptor blockade impairs extinction of naloxone-precipitated conditioned place aversion in acute morphine-treated rats by suppressing ERK and CREB phosphorylation in the basolateral amygdala

    PubMed Central

    Wang, Wei-Sheng; Chen, Zhong-Guo; Liu, Wen-Tao; Chi, Zhi-Qiang; He, Ling; Liu, Jing-Gen

    2015-01-01

    BACKGROUND AND PURPOSE Substantial evidence shows that negative reinforcement resulting from the aversive affective consequences of opiate withdrawal may play a crucial role in drug relapse. Understanding the mechanisms underlying the loss (extinction) of conditioned aversion of drug withdrawal could facilitate the treatment of drug addiction. EXPERIMENTAL APPROACH Naloxone-induced conditioned place aversion (CPA) of Sprague-Dawley rats was used to measure conditioned aversion. An NMDA receptor antagonist and MAPK kinase inhibitor were applied through intracranial injections. The phosphorylation of ERK and cAMP response element-binding protein (CREB) was detected using Western blot. KEY RESULTS The extinction of CPA behaviour increased the phosphorylation of ERK and CREB in the dorsal hippocampus (DH) and basolateral amygdala (BLA), but not in the central amygdala (CeA). Intra-DH injection of AP5 or intra-BLA injection of AP-5 or U0126 before extinction training significantly attenuated ERK and CREB phosphorylation in the BLA and impaired the extinction of CPA behaviour. Although intra-DH injections of AP-5 attenuated extinction training-induced activation of the ERK-CREB pathway in the BLA, intra-BLA injection of AP5 had no effect on extinction training-induced activation of the ERK-CREB pathway in the DH. CONCLUSIONS AND IMPLICATIONS These results suggest that activation of ERK and CREB in the BLA and DH is involved in the extinction of CPA behaviour and that the DH, via a direct or indirect pathway, modulates the activity of ERK and CREB in the BLA through activation of NMDA receptors after extinction training. Understanding the mechanisms underlying the extinction of conditioned aversion could facilitate the treatment of drug addiction. LINKED ARTICLES This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2 PMID:24597568

  20. Chronic traumatic stress impairs memory in mice: Potential roles of acetylcholine, neuroinflammation and corticotropin releasing factor expression in the hippocampus.

    PubMed

    Bhakta, Ami; Gavini, Kartheek; Yang, Euitaek; Lyman-Henley, Lani; Parameshwaran, Kodeeswaran

    2017-09-29

    Chronic stress in humans can result in multiple adverse psychiatric and neurobiological outcomes, including memory deficits. These adverse outcomes can be more severe if each episode of stress is very traumatic. When compared to acute or short term stress relatively little is known about the effects of chronic traumatic stress on memory and molecular changes in hippocampus, a brain area involved in memory processing. Here we studied the effects of chronic traumatic stress in mice by exposing them to adult Long Evan rats for 28 consecutive days and subsequently analyzing behavioral outcomes and the changes in the hippocampus. Results show that stressed mice developed memory deficits when assayed with radial arm maze tasks. However, chronic traumatic stress did not induce anxiety, locomotor hyperactivity or anhedonia. In the hippocampus of stressed mice interleukin-1β protein expression was increased along with decreased corticotropin releasing hormone (CRH) gene expression. Furthermore, there was a reduction in acetylcholine levels in the hippocampus of stressed mice. There were no changes in brain derived neurotrophic factor (BDNF) or nerve growth factor (NGF) levels in the hippocampus of stressed mice. Gene expression of immediate early genes (Zif268, Arc, C-Fos) as well as glucocorticoid and mineralocorticoid receptors were also not affected by chronic stress. These data demonstrate that chronic traumatic stress followed by a recovery period might lead to development of resilience resulting in the development of selected, most vulnerable behavioral alterations and molecular changes in the hippocampus. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Duloxetine Reduces Oxidative Stress, Apoptosis, and Ca(2+) Entry Through Modulation of TRPM2 and TRPV1 Channels in the Hippocampus and Dorsal Root Ganglion of Rats.

    PubMed

    Demirdaş, Arif; Nazıroğlu, Mustafa; Övey, İshak Suat

    2016-07-21

    Overload of Ca(2+) entry and excessive oxidative stress in neurons are the two main causes of depression. Activation of transient receptor potential (TRP) vanilloid type 1 (TRPV1) and TRP melastatin 2 (TRPM2) during oxidative stress has been linked to neuronal survival. Duloxetine (DULOX) in neurons reduced the effects of Ca(2+) entry and reactive oxygen species (ROS) through glutamate receptors, and this reduction of effects may also occur through TRPM2 and TRPV1 channels. In order to better characterize the actions of DULOX in peripheral pain and hippocampal oxidative injury through modulation of TRPM2 and TRPV1, we tested the effects of DULOX on apoptosis and oxidative stress in the hippocampal and dorsal root ganglion (DRG) neurons of rats. Freshly isolated hippocampal and DRG neurons were incubated for 24 h with DULOX. In whole-cell patch-clamp and intracellular-free calcium ([Ca(2+)]) concentration (Fura-2) experiments, cumene hydroperoxide and ADP-ribose-induced TRPM2 currents in the neurons were inhibited by N-(p-amylcinnamoyl) anthranilic acid (ACA) and capsaicin-induced TRPV1 currents were inhibited by capsazepine (CPZ) incubations. TRPM2 and TRPV1 channel current densities, [Ca(2+)] concentration, apoptosis, caspase 3, caspase 9, mitochondrial depolarization, and intracellular ROS production values in the neurons were lower in the DULOX group than in controls. In addition, the above values were further decreased by DULOX + CPZ and DULOX + ACA treatments. In conclusion, TRPM2 and TRPV1 channels are involved in Ca(2+) entry-induced neuronal death and modulation of the activity of these channels by DULOX treatment may account for their neuroprotective activity against apoptosis, excessive ROS production, and Ca(2+) entry.

  2. Lanthanum chloride impairs memory, decreases pCaMK IV, pMAPK and pCREB expression of hippocampus in rats.

    PubMed

    Yang, Jinghua; Liu, Qiufang; Zhang, Lifeng; Wu, Shengwen; Qi, Ming; Lu, Shuai; Xi, Qi; Cai, Yuan

    2009-10-28

    Surveys have reported that rare-earth elements (REEs) could impair cognitive functions of children. Experimental studies have shown the neurological adverse effects of REEs on animals. However, the mechanism underlying these impairments is unclear. Lanthanum is often selected to study the effects of REEs. The purpose of this study was to investigate the memory impairment induced by lanthanum chloride (LaCl3) exposure and the possible mechanism from the aspects of expression of CREB signal pathway and synaptic ultrastructure in the hippocampus. Lactational rats were exposed to 0%, 0.25%, 0.50%, and 1.0% LaCl3 in drinking water, respectively. Their offspring were exposed to LaCl3 by parental lactation for 3 weeks and then administrated with 0%, 0.25%, 0.50% and 1.0% LaCl3 in drinking water for 1 month. The results showed that 0.25%, 0.50%, and 1.0% LaCl3 exposure could significantly impair memory of young rats. Hippocampal pCaMK IV, pMAPK, pCREB, c-fos and egr1 expression were decreased significantly, and synaptic ultrastructure was negatively affected after LaCl3 exposure. These results indicate that LaCl3 exposure impairs memory of rats and this impairment may be attributed to the lower levels of pCaMK IV, pMAPK, pCREB, c-fos and egr1 expression and change of synaptic ultrastructure in hippocampus.

  3. The hormone therapy, Premarin, impairs hippocampus-dependent spatial learning and memory and reduces activation of new granule neurons in response to memory in female rats.

    PubMed

    Barha, Cindy K; Galea, Liisa A M

    2013-03-01

    Estrogens have been implicated as possible therapeutic agents for improving cognition in postmenopausal women and have been linked to neurodegenerative disorders such as Alzheimer's disease. However, the utility of Premarin (Wyeth Pharmaceuticals, Markham, ON, Canada), a conjugated equine estrogen and the most commonly prescribed hormone therapy, has recently been questioned. The purpose of this study was to investigate the effects of Premarin at 2 different doses (10 or 20 μg) on hippocampus-dependent spatial learning and memory, hippocampal neurogenesis, and new neuronal activation using a rodent model of surgical menopause. Rats were treated daily with subcutaneous injections of Premarin and trained on the spatial working/reference memory version of the radial arm maze. Premarin impaired spatial reference and working learning and memory, increased hippocampal neurogenesis, but either decreased or increased activation of new neurons in response to memory retrieval as indexed by the expression of the immediate early gene product zif268, depending on the maturity of cells examined. This activation of new neurons was related to impaired performance in Premarin-treated but not control-treated female rats. These results indicate that Premarin may be impairing hippocampus-dependent learning and memory by negatively altering the neurogenic environment in the dentate gyrus thus disrupting normal activity of new neurons.

  4. Caffeine consumption prevents memory impairment, neuronal damage, and adenosine A2A receptors upregulation in the hippocampus of a rat model of sporadic dementia.

    PubMed

    Espinosa, Janaína; Rocha, Andreia; Nunes, Fernanda; Costa, Marcelo S; Schein, Vanessa; Kazlauckas, Vanessa; Kalinine, Eduardo; Souza, Diogo O; Cunha, Rodrigo A; Porciúncula, Lisiane O

    2013-01-01

    Intracerebroventricular (icv) streptozotocin (STZ) administration induces pathological and behavioral alterations similar to those observed in Alzheimer's disease (AD) and is thus considered an experimental model of sporadic AD. Since caffeine (an adenosine receptor antagonist) and selective antagonists of adenosine A2A receptors modify the course of memory impairment in different amyloid-β-based experimental models of AD, we now tested the impact of caffeine on STZ-induced dementia and associated neurodegeneration in the hippocampus as well as on the expression and density of adenosine receptors. Adult male rats received a bilateral infusion of saline or STZ (3 mg/kg, icv), which triggered memory deficits after four weeks, as gauged by impaired object recognition memory. This was accompanied by a reduced NeuN immunoreactivity in the hippocampal CA1 region and an increased expression and density of adenosine A2A receptors (A2AR), but not A1R, in the hippocampus. Caffeine consumption (1 g/L in the drinking water starting 2 weeks before the STZ challenge) prevented the STZ-induced memory impairment and neurodegeneration as well as the upregulation of A2AR. These findings provide the first demonstration that caffeine prevents sporadic dementia and implicate the control of central A2AR as its likely mechanism of action.

  5. Loss of Predominant Shank3 Isoforms Results in Hippocampus-Dependent Impairments in Behavior and Synaptic Transmission

    PubMed Central

    Kouser, Mehreen; Speed, Haley E.; Dewey, Colleen M.; Reimers, Jeremy M.; Widman, Allie J.; Gupta, Natasha; Liu, Shunan; Jaramillo, Thomas C.; Bangash, Muhammad; Xiao, Bo; Worley, Paul F.

    2013-01-01

    The Shank3 gene encodes a scaffolding protein that anchors multiple elements of the postsynaptic density at the synapse. Previous attempts to delete the Shank3 gene have not resulted in a complete loss of the predominant naturally occurring Shank3 isoforms. We have now characterized a homozygous Shank3 mutation in mice that deletes exon 21, including the Homer binding domain. In the homozygous state, deletion of exon 21 results in loss of the major naturally occurring Shank3 protein bands detected by C-terminal and N-terminal antibodies, allowing us to more definitively examine the role of Shank3 in synaptic function and behavior. This loss of Shank3 leads to an increased localization of mGluR5 to both synaptosome and postsynaptic density-enriched fractions in the hippocampus. These mice exhibit a decrease in NMDA/AMPA excitatory postsynaptic current ratio in area CA1 of the hippocampus, reduced long-term potentiation in area CA1, and deficits in hippocampus-dependent spatial learning and memory. In addition, these mice also exhibit motor-coordination deficits, hypersensitivity to heat, novelty avoidance, altered locomotor response to novelty, and minimal social abnormalities. These data suggest that Shank3 isoforms are required for normal synaptic transmission/plasticity in the hippocampus, as well as hippocampus-dependent spatial learning and memory. PMID:24259569

  6. Postnatal dysregulation of Notch signal disrupts dendrite development of adult-born neurons in the hippocampus and contributes to memory impairment

    PubMed Central

    Ding, Xue-Feng; Gao, Xiang; Ding, Xin-Chun; Fan, Ming; Chen, Jinhui

    2016-01-01

    Deficits in the Notch pathway are involved in a number of neurologic diseases associated with mental retardation or/and dementia. The mechanisms by which Notch dysregulation are associated with mental retardation and dementia are poorly understood. We found that Notch1 is highly expressed in the adult-born immature neurons in the hippocampus of mice. Retrovirus mediated knockout of notch1 in single adult-born immature neurons decreases mTOR signaling and compromises their dendrite morphogenesis. In contrast, overexpression of Notch1 intracellular domain (NICD), to constitutively activate Notch signaling in single adult-born immature neurons, promotes mTOR signaling and increases their dendrite arborization. Using a unique genetic approach to conditionally and selectively knockout notch 1 in the postnatally born immature neurons in the hippocampus decreases mTOR signaling, compromises their dendrite morphogenesis, and impairs spatial learning and memory. Conditional overexpression of NICD in the postnatally born immature neurons in the hippocampus increases mTOR signaling and promotes dendrite arborization. These data indicate that Notch signaling plays a critical role in dendrite development of immature neurons in the postnatal brain, and dysregulation of Notch signaling in the postnatally born neurons disrupts their development and thus contributes to the cognitive deficits associated with neurological diseases. PMID:27173138

  7. Prolonged duration of isoflurane anesthesia impairs spatial recognition memory through the activation of JNK1/2 in the hippocampus of mice.

    PubMed

    Jiang, Shan; Miao, Bei; Chen, Ying

    2017-02-24

    Postoperative cognitive dysfunction is a frequent complication with surgery and anesthesia, and the underlying mechanism is unclear. Our aim was to investigate the effect of different durations of isoflurane anesthesia on spatial recognition memory and activation of JNK1/2 in the hippocampus of mice. In the present study, adult male mice were anesthetized with isoflurane for different durations (1.5% isoflurane for 1, 2, and 4 h). Spatial recognition memory was determined using spontaneous alternation and two-trial recognition memory in Y-maze at 24 h after anesthesia. The activation of JNK1/2 in the hippocampus was tested using western blot. Mice treated with isoflurane for 4 h showed significantly decreased spontaneous alternations and decreased exploration parameters compared with the no anesthesia group, but this was not observed in mice treated with isoflurane for 1 or 2 h. The protein levels of p-JNK1/2 in the hippocampus were significantly increased at 10 min after isoflurane anesthesia for 1, 2, and 4 h compared with no anesthesia. However, only isoflurane anesthesia for 4 h still increased JNK1/2 and p-JNK1/2 levels at 24 h after anesthesia. We concluded that prolonged duration of isoflurane anesthesia maintained the activation of JNK1/2, which led to memory impairment at 24 h after anesthesia.

  8. Tiliacora triandra, an Anti-Intoxication Plant, Improves Memory Impairment, Neurodegeneration, Cholinergic Function, and Oxidative Stress in Hippocampus of Ethanol Dependence Rats

    PubMed Central

    Phunchago, Nattaporn; Wattanathorn, Jintanaporn; Chaisiwamongkol, Kowit

    2015-01-01

    Oxidative stress plays an important role in brain dysfunctions induced by alcohol. Since less therapeutic agent against cognitive deficit and brain damage induced by chronic alcohol consumption is less available, we aimed to assess the effect of Tiliacora triandra extract, a plant possessing antioxidant activity, on memory impairment, neuron density, cholinergic function, and oxidative stress in hippocampus of alcoholic rats. Male Wistar rats were induced ethanol dependence condition by semivoluntary intake of alcohol for 15 weeks. Alcoholic rats were orally given T. triandra at doses of 100, 200, and 400 mg·kg−1BW for 14 days. Memory assessment was performed every 7 days while neuron density, activities of AChE, SOD, CAT, and GSH-Px and, MDA level in hippocampus were assessed at the end of study. Interestingly, the extract mitigated the increased escape latency, AChE and MDA level. The extract also mitigated the decreased retention time, SOD, CAT, and GSH-Px activities, and neurons density in hippocampus induced by alcohol. These data suggested that the extract improved memory deficit in alcoholic rats partly via the decreased oxidative stress and the suppression of AChE. Therefore, T. triandra is the potential reagent for treating brain dysfunction induced by alcohol. However, further researches are necessary to understand the detail mechanism and possible active ingredient. PMID:26180599

  9. Fluoride and Arsenic Exposure Impairs Learning and Memory and Decreases mGluR5 Expression in the Hippocampus and Cortex in Rats

    PubMed Central

    Jiang, Shoufang; Su, Jing; Yao, Sanqiao; Zhang, Yanshu; Cao, Fuyuan; Wang, Fei; Wang, Huihui; Li, Jun; Xi, Shuhua

    2014-01-01

    Fluoride and arsenic are two common inorganic contaminants in drinking water that are associated with impairment in child development and retarded intelligence. The present study was conducted to explore the effects on spatial learning, memory, glutamate levels, and group I metabotropic glutamate receptors (mGluRs) expression in the hippocampus and cortex after subchronic exposure to fluoride, arsenic, and a fluoride and arsenic combination in rats. Weaned male Sprague-Dawley rats were assigned to four groups. The control rats drank tap water. Rats in the three exposure groups drank water with sodium fluoride (120 mg/L), sodium arsenite (70 mg/L), and a sodium fluoride (120 mg/L) and sodium arsenite (70 mg/L) combination for 3 months. Spatial learning and memory was measured in Morris water maze. mGluR1 and mGluR5 mRNA and protein expression in the hippocampus and cortex was detected using RT-PCR and Western blot, respectively. Compared with controls, learning and memory ability declined in rats that were exposed to fluoride and arsenic both alone and combined. Combined fluoride and arsenic exposure did not have a more pronounced effect on spatial learning and memory compared with arsenic and fluoride exposure alone. Compared with controls, glutamate levels decreased in the hippocampus and cortex of rats exposed to fluoride and combined fluoride and arsenic, and in cortex of arsenic-exposed rats. mGluR5 mRNA and protein expressions in the hippocampus and mGluR5 protein expression in the cortex decreased in rats exposed to arsenic alone. Interestingly, compared with fluoride and arsenic exposure alone, fluoride and arsenic combination decreased mGluR5 mRNA expression in the cortex and protein expression in the hippocampus, suggesting a synergistic effect of fluoride and arsenic. These data indicate that fluoride and arsenic, either alone or combined, can decrease learning and memory ability in rats. The mechanism may be associated with changes of glutamate level and

  10. Hippocampus-Dependent Goal Localization by Head-Fixed Mice in Virtual Reality.

    PubMed

    Sato, Masaaki; Kawano, Masako; Mizuta, Kotaro; Islam, Tanvir; Lee, Min Goo; Hayashi, Yasunori

    2017-01-01

    The demonstration of the ability of rodents to navigate in virtual reality (VR) has made it an important behavioral paradigm for studying spatially modulated neuronal activity in these animals. However, their behavior in such simulated environments remains poorly understood. Here, we show that encoding and retrieval of goal location memory in mice head-fixed in VR depends on the postsynaptic scaffolding protein Shank2 and the dorsal hippocampus. In our newly developed virtual cued goal location task, a head-fixed mouse moves from one end of a virtual linear track to seek rewards given at a target location along the track. The mouse needs to visually recognize the target location and stay there for a short period of time to receive the reward. Transient pharmacological blockade of fast glutamatergic synaptic transmission in the dorsal hippocampus dramatically and reversibly impaired performance of this task. Encoding and updating of virtual cued goal location memory was impaired in mice deficient in the postsynaptic scaffolding protein Shank2, a mouse model of autism that exhibits impaired spatial learning in a real environment. These results highlight the crucial roles of the dorsal hippocampus and postsynaptic protein complexes in spatial learning and navigation in VR.

  11. Hippocampus-Dependent Goal Localization by Head-Fixed Mice in Virtual Reality

    PubMed Central

    Kawano, Masako; Mizuta, Kotaro; Islam, Tanvir; Lee, Min Goo; Hayashi, Yasunori

    2017-01-01

    Abstract The demonstration of the ability of rodents to navigate in virtual reality (VR) has made it an important behavioral paradigm for studying spatially modulated neuronal activity in these animals. However, their behavior in such simulated environments remains poorly understood. Here, we show that encoding and retrieval of goal location memory in mice head-fixed in VR depends on the postsynaptic scaffolding protein Shank2 and the dorsal hippocampus. In our newly developed virtual cued goal location task, a head-fixed mouse moves from one end of a virtual linear track to seek rewards given at a target location along the track. The mouse needs to visually recognize the target location and stay there for a short period of time to receive the reward. Transient pharmacological blockade of fast glutamatergic synaptic transmission in the dorsal hippocampus dramatically and reversibly impaired performance of this task. Encoding and updating of virtual cued goal location memory was impaired in mice deficient in the postsynaptic scaffolding protein Shank2, a mouse model of autism that exhibits impaired spatial learning in a real environment. These results highlight the crucial roles of the dorsal hippocampus and postsynaptic protein complexes in spatial learning and navigation in VR. PMID:28484738

  12. Dexmedetomidine ameliorates intracerebral hemorrhage-induced memory impairment by inhibiting apoptosis and enhancing brain-derived neurotrophic factor expression in the rat hippocampus.

    PubMed

    Hwang, Lakkyong; Choi, In-Young; Kim, Sung-Eun; Ko, Il-Gyu; Shin, Mal-Soon; Kim, Chang-Ju; Kim, Sang-Hoon; Jin, Jun-Jang; Chung, Jun-Young; Yi, Jae-Woo

    2013-05-01

    Intracerebral hemorrhage (ICH) is a severe type of stroke causing neurological dysfunction with a high mortality rate. Dexmedetomidine is an agonist for α2‑adrenoreceptors with sedative, anxiolytic, analgesic and anesthetic effects. In the present study, we investigated the effects of dexmedetomidine on short‑term and spatial learning memory, as well as its effects on apoptosis following the induction of ICH in rats. A rat model of IHC was created by an injection of collagenase into the hippocampus using a stereotaxic instrument. Dexmedetomidine was administered intraperitoneally daily for 14 consecutive days, commencing 1 day after the induction of ICH. The step‑down avoidance test for short‑term memory and the radial 8‑arm maze test for spatial learning memory were conducted. Terminal deoxynucleotidyl transferase‑mediated dUTP nick end-labeling (TUNEL) assay, immunohistochemistry for caspase‑3, and western blot analysis for Bcl‑2, Bax, Bid and caspase-3 expression were performed for the detection of apoptosis in the hippocampus. Western blot analysis for the brain‑derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB) was also performed for the detection of cell survival in the hippocampus. The induction of ICH deteriorated short‑term and spatial learning memory, increased apoptosis and suppressed BDNF and TrkB expression in the hippocampus. Treatment with dexmedetomidine ameliorated the ICH‑induced impairment of short‑term and spatial learning memory by suppressing apoptosis and enhancing BDNF and TrkB expression. In the normal rats, dexmedetomidine exerted no significant effects on memory function and apoptosis. The present results suggest the possibility that dexmedetomidine may be used as a therapeutic agent for the conservation of memory function in stroke patients.

  13. Fornix White Matter is Correlated with Resting-State Functional Connectivity of the Thalamus and Hippocampus in Healthy Aging but Not in Mild Cognitive Impairment - A Preliminary Study.

    PubMed

    Kehoe, Elizabeth G; Farrell, Dervla; Metzler-Baddeley, Claudia; Lawlor, Brian A; Kenny, Rose Anne; Lyons, Declan; McNulty, Jonathan P; Mullins, Paul G; Coyle, Damien; Bokde, Arun L

    2015-01-01

    In this study, we wished to examine the relationship between the structural connectivity of the fornix, a white matter (WM) tract in the limbic system, which is affected in amnestic mild cognitive impairment (aMCI) and Alzheimer's disease, and the resting-state functional connectivity (FC) of two key related subcortical structures, the thalamus, and hippocampus. Twenty-two older healthy controls (HC) and 18 older adults with aMCI underwent multi-modal MRI scanning. The fornix was reconstructed using constrained-spherical deconvolution-based tractography. The FC between the thalamus and hippocampus was calculated using a region-of-interest approach from which the mean time series were exacted and correlated. Diffusion tensor imaging measures of the WM microstructure of the fornix were correlated against the Fisher Z correlation values from the FC analysis. There was no difference between the groups in the fornix WM measures, nor in the resting-state FC of the thalamus and hippocampus. We did however find that the relationship between functional and structural connectivity differed significantly between the groups. In the HCs, there was a significant positive association between linear diffusion (CL) in the fornix and the FC of the thalamus and hippocampus, however, there was no relationship between these measures in the aMCI group. These preliminary findings suggest that in aMCI, the relationship between the functional and structural connectivity of regions of the limbic system may be significantly altered compared to healthy ageing. The combined use of diffusion weighted imaging and functional MRI may advance our understanding of neural network changes in aMCI, and elucidate subtle changes in the relationship between structural and functional brain networks.

  14. Inhibition of indoleamine 2,3-dioxygenase 1/2 prevented cognitive impairment and energetic metabolism changes in the hippocampus of adult rats subjected to polymicrobial sepsis.

    PubMed

    Comim, Clarissa M; Freiberger, Viviane; Ventura, Letícia; Mina, Francielle; Ferreira, Gabriela K; Michels, Monique; Generoso, Jaqueline S; Streck, Emílio L; Quevedo, João; Barichello, Tatiana; Dal-Pizzol, Felipe

    2017-04-15

    Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection that may affect the brain. We investigated the role of indoleamine 2,3-dioxygenase (IDO-1/2) inhibition on long-term memory and energetic metabolism after experimental sepsis by caecal ligation and perforation (CLP). Experimental sepsis increased the activity of complexes I, II-III and IV at 24h after CLP, and IDO-1/2 inhibition normalized the activity of these complexes in the hippocampus. Wistar rats presented impairment of habituation and aversive memories 10days after CLP. Adjuvant treatment with the IDO inhibitor prevented long-term cognitive impairment triggered by sepsis. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Prenatal Stress Impairs Spatial Learning and Memory Associated with Lower mRNA Level of the CAMKII and CREB in the Adult Female Rat Hippocampus.

    PubMed

    Sun, Hongli; Wu, Haibin; Liu, Jianping; Wen, Jun; Zhu, Zhongliang; Li, Hui

    2017-02-25

    Prenatal stress (PS) results in various behavioral and emotional alterations observed in later life. In particular, PS impairs spatial learning and memory processes but the underlying mechanism involved in this pathogenesis still remains unknown. Here, we reported that PS lowered the body weight in offspring rats, particularly in female rats, and impaired spatial learning and memory of female offspring rats in the Morris water maze. Correspondingly, the decreased CaMKII and CREB mRNA in the hippocampus were detected in prenatally stressed female offspring, which partially explained the effect of PS on the spatial learning and memory. Our findings suggested that CaMKII and CREB may be involved in spatial learning and memory processes in the prenatally stressed adult female offspring.

  16. Honokiol abrogates chronic restraint stress-induced cognitive impairment and depressive-like behaviour by blocking endoplasmic reticulum stress in the hippocampus of mice.

    PubMed

    Jangra, Ashok; Dwivedi, Shubham; Sriram, Chandra Shaker; Gurjar, Satendra Singh; Kwatra, Mohit; Sulakhiya, Kunjbihari; Baruah, Chandana C; Lahkar, Mangala

    2016-01-05

    The primary objective of our study is to investigate the neuroprotective efficacy of honokiol and imipramine against restraint stress (RS)-induced cognitive impairment and depressive-like behaviour in mice. We examined whether the neuroprotective activity of honokiol and imipramine mediates through the inhibition of endoplasmic reticulum stress. Adult Swiss albino mice were restrained for 6h/day for 28 days. Honokiol (3 and 10mg/kg) and Imipramine (10 and 30mg/kg) were administered for last 7 days to the different groups. Cognitive function was assessed by Morris water maze and novel object recognition test. Forced swimming test and tail suspension test were performed to evaluate the restraint stress-induced depressive-like behaviour. Proinflammatory cytokines, brain-derived neurotrophic factor, and ER stress markers i.e. 78-kDa glucose-regulated protein (GRP78) and C/EBP homologous protein (CHOP) were quantified in the hippocampus. We observed cognitive impairment and depressive-like behaviour in RS-exposed animals. Honokiol (10mg/kg) treated group depicted marked reduction in cognitive impairment and depressive-like behaviour. However, imipramine (10 and 30mg/kg) prevented the depressive-like behaviour but failed to prevent RS-induced cognitive impairment. Moreover, proinflammatory cytokines, GRP78 and CHOP were elevated in the hippocampus of stressed mice as compared to unstressed mice. Honokiol (10mg/kg) significantly prevented the RS-induced elevated levels of proinflammatory cytokines and endoplasmic reticulum stress markers. Our results clearly suggest the beneficial potential of honokiol in restraint stress through inhibition of proinflammatory cytokines and endoplasmic reticulum stress. Honokiol could be an intriguing therapeutic approach in endoplasmic reticulum stress related neuro-pathophysiological conditions. Copyright © 2015. Published by Elsevier B.V.

  17. Hippocampus and two-way active avoidance conditioning: Contrasting effects of cytotoxic lesion and temporary inactivation.

    PubMed

    Wang, Jia; Bast, Tobias; Wang, Yu-Cong; Zhang, Wei-Ning

    2015-12-01

    Hippocampal lesions tend to facilitate two-way active avoidance (2WAA) conditioning, where rats learn to cross to the opposite side of a conditioning chamber to avoid a tone-signaled footshock. This classical finding has been suggested to reflect that hippocampus-dependent place/context memory inhibits 2WAA (a crossing response to the opposite side is inhibited by the memory that this is the place where a shock was received on the previous trial). However, more recent research suggests other aspects of hippocampal function that may support 2WAA learning. More specifically, the ventral hippocampus has been shown to contribute to behavioral responses to aversive stimuli and to positively modulate the meso-accumbens dopamine system, whose activation has been implicated in 2WAA learning. Permanent hippocampal lesions may not reveal these contributions because, following complete and permanent loss of hippocampal output, other brain regions may mediate these processes or because deficits could be masked by lesion-induced extra-hippocampal changes, including an upregulation of accumbal dopamine transmission. Here, we re-examined the hippocampal role in 2WAA learning in Wistar rats, using permanent NMDA-induced neurotoxic lesions and temporary functional inhibition by muscimol or tetrodotoxin (TTX) infusion. Complete hippocampal lesions tended to facilitate 2WAA learning, whereas ventral (VH) or dorsal hippocampal (DH) lesions had no effect. In contrast, VH or DH muscimol or TTX infusions impaired 2WAA learning. Ventral infusions caused an immediate impairment, whereas after dorsal infusions rats showed intact 2WAA learning for 40-50 min, before a marked deficit emerged. These data show that functional inhibition of ventral hippocampus disrupts 2WAA learning, while the delayed impairment following dorsal infusions may reflect the time required for drug diffusion to ventral hippocampus. Overall, using temporary functional inhibition, our study shows that the ventral

  18. Resting-State Connectivity of the Left Frontal Cortex to the Default Mode and Dorsal Attention Network Supports Reserve in Mild Cognitive Impairment.

    PubMed

    Franzmeier, Nicolai; Göttler, Jens; Grimmer, Timo; Drzezga, Alexander; Áraque-Caballero, Miguel A; Simon-Vermot, Lee; Taylor, Alexander N W; Bürger, Katharina; Catak, Cihan; Janowitz, Daniel; Müller, Claudia; Duering, Marco; Sorg, Christian; Ewers, Michael

    2017-01-01

    Reserve refers to the phenomenon of relatively preserved cognition in disproportion to the extent of neuropathology, e.g., in Alzheimer's disease. A putative functional neural substrate underlying reserve is global functional connectivity of the left lateral frontal cortex (LFC, Brodmann Area 6/44). Resting-state fMRI-assessed global LFC-connectivity is associated with protective factors (education) and better maintenance of memory in mild cognitive impairment (MCI). Since the LFC is a hub of the fronto-parietal control network that regulates the activity of other networks, the question arises whether LFC-connectivity to specific networks rather than the whole-brain may underlie reserve. We assessed resting-state fMRI in 24 MCI and 16 healthy controls (HC) and in an independent validation sample (23 MCI/32 HC). Seed-based LFC-connectivity to seven major resting-state networks (i.e., fronto-parietal, limbic, dorsal-attention, somatomotor, default-mode, ventral-attention, visual) was computed, reserve was quantified as residualized memory performance after accounting for age and hippocampal atrophy. In both samples of MCI, LFC-activity was anti-correlated with the default-mode network (DMN), but positively correlated with the dorsal-attention network (DAN). Greater education predicted stronger LFC-DMN-connectivity (anti-correlation) and LFC-DAN-connectivity. Stronger LFC-DMN and LFC-DAN-connectivity each predicted higher reserve, consistently in both MCI samples. No associations were detected for LFC-connectivity to other networks. These novel results extend our previous findings on global functional connectivity of the LFC, showing that LFC-connectivity specifically to the DAN and DMN, two core memory networks, enhances reserve in the memory domain in MCI.

  19. Contextual learning requires synaptic AMPA receptor delivery in the hippocampus

    PubMed Central

    Mitsushima, Dai; Ishihara, Kouji; Sano, Akane; Kessels, Helmut W.; Takahashi, Takuya

    2011-01-01

    The hippocampus plays a central role in learning and memory. Although synaptic delivery of AMPA-type glutamate receptors (AMPARs) contributes to experience-dependent synaptic strengthening, its role in hippocampus-dependent learning remains elusive. By combining viral-mediated in vivo gene delivery with in vitro patch-clamp recordings, we found that the inhibitory avoidance task, a hippocampus-dependent contextual fear-learning paradigm, delivered GluR1-containing AMPARs into CA3-CA1 synapses of the dorsal hippocampus. To block the synaptic delivery of endogenous AMPARs, we expressed a fragment of the GluR1-cytoplasmic tail (the 14-aa GluR1 membrane-proximal region with two serines mutated to phospho-mimicking aspartates: MPR-DD). MPR-DD prevented learning-driven synaptic AMPAR delivery in CA1 neurons. Bilateral expression of MPR-DD in the CA1 region of the rat impaired inhibitory avoidance learning, indicating that synaptic GluR1 trafficking in the CA1 region of the hippocampus is required for encoding contextual fear memories. The fraction of CA1 neurons that underwent synaptic strengthening positively correlated with the performance in the inhibitory avoidance fear memory task. These data suggest that the robustness of a contextual memory depends on the number of hippocampal neurons that participate in the encoding of a memory trace. PMID:21746893

  20. Contextual learning requires synaptic AMPA receptor delivery in the hippocampus.

    PubMed

    Mitsushima, Dai; Ishihara, Kouji; Sano, Akane; Kessels, Helmut W; Takahashi, Takuya

    2011-07-26

    The hippocampus plays a central role in learning and memory. Although synaptic delivery of AMPA-type glutamate receptors (AMPARs) contributes to experience-dependent synaptic strengthening, its role in hippocampus-dependent learning remains elusive. By combining viral-mediated in vivo gene delivery with in vitro patch-clamp recordings, we found that the inhibitory avoidance task, a hippocampus-dependent contextual fear-learning paradigm, delivered GluR1-containing AMPARs into CA3-CA1 synapses of the dorsal hippocampus. To block the synaptic delivery of endogenous AMPARs, we expressed a fragment of the GluR1-cytoplasmic tail (the 14-aa GluR1 membrane-proximal region with two serines mutated to phospho-mimicking aspartates: MPR-DD). MPR-DD prevented learning-driven synaptic AMPAR delivery in CA1 neurons. Bilateral expression of MPR-DD in the CA1 region of the rat impaired inhibitory avoidance learning, indicating that synaptic GluR1 trafficking in the CA1 region of the hippocampus is required for encoding contextual fear memories. The fraction of CA1 neurons that underwent synaptic strengthening positively correlated with the performance in the inhibitory avoidance fear memory task. These data suggest that the robustness of a contextual memory depends on the number of hippocampal neurons that participate in the encoding of a memory trace.

  1. Neuroprotective effect of the aminoestrogen prolame against impairment of learning and memory skills in rats injected with amyloid-β-25-35 into the hippocampus.

    PubMed

    Limón, Daniel; Díaz, Alfonso; Hernandez, Monserrat; Fernandez-G, Juan M; Torres-Martínez, Ana C; Pérez-Severiano, Francisca; Rendón-Huerta, Erika P; Montaño, Luis F; Guevara, Jorge

    2012-06-15

    Alzheimer's disease (AD) is a neurodegenerative disorder caused by the deposition of the amyloid-beta peptide (Aβ) in senile plaques and cerebral vasculature. Its neurotoxic mechanisms are associated with the generation of oxidative stress and reactive astrogliosis that cause neuronal death and memory impairment. Estrogens reduce the rate of Azheimer's disease because of their antioxidant activity. Prolame (N-(3-hydroxy-1,3,5(10)-estratrien-17β-yl)-3-hydroxypropylamine) is an aminoestrogen with estrogenic and antithrombotic effects. In our study we evaluated the role of prolame on Aβ(25-35)-caused oxidative stress, reactive astrogliosis, and impairment of spatial memory(.) The Aβ(25-35) (100 μM/μl) or vehicle was injected into the CA1 subfield of the hippocampus of the rat. The subcutaneous injection of prolame (400 μl, 50 nM) or sesame oil (400 μl) started 1 day before the Aβ(25-35) injection and was continued for another 29 days. The results showed a significant impairment of spatial memory evident 30 days after the Aβ(25-35) injection. The prolame treatment significantly reduced spatial-memory impairment and decreased lipid peroxidation, reactive oxygen species, and reactive gliosis. It also restored the eNOS and nNOS expression to normal levels. In conclusion the aminoestrogen prolame should be considered as an alternative in the treatment of Alzheimer's disease.

  2. Consumption of molecular hydrogen prevents the stress-induced impairments in hippocampus-dependent learning tasks during chronic physical restraint in mice.

    PubMed

    Nagata, Kazufumi; Nakashima-Kamimura, Naomi; Mikami, Toshio; Ohsawa, Ikuroh; Ohta, Shigeo

    2009-01-01

    We have reported that hydrogen (H(2)) acts as an efficient antioxidant by gaseous rapid diffusion. When water saturated with hydrogen (hydrogen water) was placed into the stomach of a rat, hydrogen was detected at several microM level in blood. Because hydrogen gas is unsuitable for continuous consumption, we investigated using mice whether drinking hydrogen water ad libitum, instead of inhaling hydrogen gas, prevents cognitive impairment by reducing oxidative stress. Chronic physical restraint stress to mice enhanced levels of oxidative stress markers, malondialdehyde and 4-hydroxy-2-nonenal, in the brain, and impaired learning and memory, as judged by three different methods: passive avoidance learning, object recognition task, and the Morris water maze. Consumption of hydrogen water ad libitum throughout the whole period suppressed the increase in the oxidative stress markers and prevented cognitive impairment, as judged by all three methods, whereas hydrogen water did not improve cognitive ability when no stress was provided. Neural proliferation in the dentate gyrus of the hippocampus was suppressed by restraint stress, as observed by 5-bromo-2'-deoxyuridine incorporation and Ki-67 immunostaining, proliferation markers. The consumption of hydrogen water ameliorated the reduced proliferation although the mechanistic link between the hydrogen-dependent changes in neurogenesis and cognitive impairments remains unclear. Thus, continuous consumption of hydrogen water reduces oxidative stress in the brain, and prevents the stress-induced decline in learning and memory caused by chronic physical restraint. Hydrogen water may be applicable for preventive use in cognitive or other neuronal disorders.

  3. Betaine attenuates memory impairment after water-immersion restraint stress and is regulated by the GABAergic neuronal system in the hippocampus.

    PubMed

    Kunisawa, Kazuo; Kido, Kiwamu; Nakashima, Natsuki; Matsukura, Takuya; Nabeshima, Toshitaka; Hiramatsu, Masayuki

    2017-02-05

    GABA mediated neuronal system regulates hippocampus-dependent memory and stress responses by controlling plasticity and neuronal excitability. Here, we demonstrate that betaine ameliorates water-immersion restraint stress (WIRS)-induced memory impairments. This improvement was inhibited by a betaine/GABA transporter-1 (GABA transporter-2: GAT2) inhibitor, NNC 05-2090. In this study, we investigated whether memory amelioration by betaine was mediated by the GABAergic neuronal system. Adult male mice were co-administered betaine and GABA receptor antagonists after WIRS. We also examined whether memory impairment after WIRS was attenuated by GABA receptor agonists. The memory functions were evaluated using a novel object recognition test 3-6 days after WIRS and/or the step-down type passive avoidance test at 7-8 days. The co-administration of the GABAA receptor antagonist bicuculline (1mg/kg) or the GABAB receptor antagonist phaclofen (10mg/kg) 1h after WIRS suppressed the memory-improving effects induced by betaine. Additionally, the administration of the GABAA receptor agonist muscimol (1mg/kg) or the GABAB receptor agonist baclofen (10mg/kg) 1h after WIRS attenuated memory impairments. These results were similar to the data observed with betaine. The treatment with betaine after WIRS significantly decreased the expression of GABA transaminase, and this effect was partially blocked by NNC 05-2090 in the hippocampus. WIRS caused a transient increase in hippocampal GABA levels and the changes after WIRS were not affected by betaine treatment in an in vivo microdialysis study. These results suggest that the beneficial effects of betaine may be mediated in part by changing the GABAergic neuronal system.

  4. A key role for nectin-1 in the ventral hippocampus in contextual fear memory.

    PubMed

    Fantin, Martina; van der Kooij, Michael A; Grosse, Jocelyn; Krummenacher, Claude; Sandi, Carmen

    2013-01-01

    Nectins are cell adhesion molecules that are widely expressed in the brain. Nectin expression shows a dynamic spatiotemporal regulation, playing a role in neural migratory processes during development. Nectin-1 and nectin-3 and their heterophilic trans-interactions are important for the proper formation of synapses. In the hippocampus, nectin-1 and nectin-3 localize at puncta adherentia junctions and may play a role in synaptic plasticity, a mechanism essential for memory and learning. We evaluated the potential involvement of nectin-1 and nectin-3 in memory consolidation using an emotional learning paradigm. Rats trained for contextual fear conditioning showed transient nectin-1-but not nectin-3-protein upregulation in synapse-enriched hippocampal fractions at about 2 h posttraining. The upregulation of nectin-1 was found exclusively in the ventral hippocampus and was apparent in the synaptoneurosomal fraction. This upregulation was induced by contextual fear conditioning but not by exposure to context or shock alone. When an antibody against nectin-1, R165, was infused in the ventral-hippocampus immediately after training, contextual fear memory was impaired. However, treatment with the antibody in the dorsal hippocampus had no effect in contextual fear memory formation. Similarly, treatment with the antibody in the ventral hippocampus did not interfere with acoustic memory formation. Further control experiments indicated that the effects of ventral hippocampal infusion of the nectin-1 antibody in contextual fear memory cannot be ascribed to memory non-specific effects such as changes in anxiety-like behavior or locomotor behavior. Therefore, we conclude that nectin-1 recruitment to the perisynaptic environment in the ventral hippocampus plays an important role in the formation of contextual fear memories. Our results suggest that these mechanisms could be involved in the connection of emotional and contextual information processed in the amygdala and dorsal

  5. A Key Role for Nectin-1 in the Ventral Hippocampus in Contextual Fear Memory

    PubMed Central

    Grosse, Jocelyn; Krummenacher, Claude; Sandi, Carmen

    2013-01-01

    Nectins are cell adhesion molecules that are widely expressed in the brain. Nectin expression shows a dynamic spatiotemporal regulation, playing a role in neural migratory processes during development. Nectin-1 and nectin-3 and their heterophilic trans-interactions are important for the proper formation of synapses. In the hippocampus, nectin-1 and nectin-3 localize at puncta adherentia junctions and may play a role in synaptic plasticity, a mechanism essential for memory and learning. We evaluated the potential involvement of nectin-1 and nectin-3 in memory consolidation using an emotional learning paradigm. Rats trained for contextual fear conditioning showed transient nectin-1—but not nectin-3—protein upregulation in synapse-enriched hippocampal fractions at about 2 h posttraining. The upregulation of nectin-1 was found exclusively in the ventral hippocampus and was apparent in the synaptoneurosomal fraction. This upregulation was induced by contextual fear conditioning but not by exposure to context or shock alone. When an antibody against nectin-1, R165, was infused in the ventral-hippocampus immediately after training, contextual fear memory was impaired. However, treatment with the antibody in the dorsal hippocampus had no effect in contextual fear memory formation. Similarly, treatment with the antibody in the ventral hippocampus did not interfere with acoustic memory formation. Further control experiments indicated that the effects of ventral hippocampal infusion of the nectin-1 antibody in contextual fear memory cannot be ascribed to memory non-specific effects such as changes in anxiety-like behavior or locomotor behavior. Therefore, we conclude that nectin-1 recruitment to the perisynaptic environment in the ventral hippocampus plays an important role in the formation of contextual fear memories. Our results suggest that these mechanisms could be involved in the connection of emotional and contextual information processed in the amygdala and dorsal

  6. Disruption of Hippocampal Neuregulin 1-ErbB4 Signaling Contributes to the Hippocampus-dependent Cognitive Impairment Induced by Isoflurane in Aged Mice

    PubMed Central

    Li, Xiao-Min; Su, Fan; Ji, Mu-Huo; Zhang, Guang-Fen; Qiu, Li-Li; Jia, Min; Gao, Jun; Xie, Zhongcong; Yang, Jian-Jun

    2014-01-01

    Background A prolonged isoflurane exposure may lead to cognitive decline in rodents. Neuregulin 1 (NRG1)-ErbB4 signaling plays a key role in the modulation of hippocampal synaptic plasticity through regulating the neurotransmission. We hypothesized hippocampal NRG1-ErbB4 signaling is involved in isoflurane-induced cognitive impairments in aged mice. Methods Fourteen-month old C57BL/6 mice were randomized to receive 100% O2 exposure, vehicle injection after 100% O2 exposure, vehicle injection after exposure to isoflurane carried by 100% O2, NRG1-β1 injection after exposure to isoflurane carried by 100% O2, and NRG1-β1 and an ErbB4 inhibitor AG1478 injection after exposure to isoflurane carried by 100% O2. Fear conditioning test was used to assess the cognitive function of mice 48 h post-exposure. The brain tissues were harvested 48 h post-exposure to determine the levels of NRG1, ErbB4, p-ErbB4, parvalbumin, and glutamic acid decarboxylase (GAD) 67 in the hippocampus using western blotting, enzyme-linked immunosorbent assay, and immunofluorescence. Results The percentage of freezing time to context was decreased from 50.28 ± 11.53% to 30.82 ± 10.00% and the hippocampal levels of NRG1, p-ErbB4/ErbB4, parvalbumin, and GAD67 were decreased from 172.79 ± 20.85 ng/g, 69.15 ± 12.20%, 101.68 ± 11.21%, and 104.71 ± 6.85%, to 112.92 ± 16.65 ng/g, 42.26 ± 9.71%, 75.89 ± 10.26%, and 73.87 ± 16.89%, respectively, after isoflurane exposure. NRG1-β1 attenuated the isoflurane-induced hippocampus-dependent cognitive impairment and the declines in the hippocampal NRG1, p-ErbB4/ErbB4, parvalbumin, and GAD67. AG1478 inhibited the NRG1-β1’s rescuing effects. Conclusions Disruption of NRG1-ErbB4 signaling in the parvalbumin-positive interneurons might, at least partially, contribute to the isoflurane-induced hippocampus-dependent cognitive impairment after exposure to isoflurane carried by 100% O2 in aged mice. PMID:24589481

  7. A Single Neonatal Injection of Ethinyl Estradiol Impairs Passive Avoidance Learning and Reduces Expression of Estrogen Receptor α in the Hippocampus and Cortex of Adult Female Rats.

    PubMed

    Shiga, Tatsuomi; Nakamura, Takahiro J; Komine, Chiaki; Goto, Yoshikuni; Mizoguchi, Yasushi; Yoshida, Midori; Kondo, Yasuhiko; Kawaguchi, Maiko

    2016-01-01

    Although perinatal exposure of female rats to estrogenic compounds produces irreversible changes in brain function, it is still unclear how the amount and timing of exposure to those substances affect learning function, or if exposure alters estrogen receptor α (ERα) expression in the hippocampus and cortex. In adult female rats, we investigated the effects of neonatal exposure to a model estrogenic compound, ethinyl estradiol (EE), on passive avoidance learning and ERα expression. Female Wistar-Imamichi rats were subcutaneously injected with oil, 0.02 mg/kg EE, 2 mg/kg EE, or 20 mg/kg 17β-estradiol within 24 h after birth. All females were tested for passive avoidance learning at the age of 6 weeks. Neonatal 0.02 mg/kg EE administration significantly disrupted passive avoidance compared with oil treatment in gonadally intact females. In a second experiment, another set of experimental females, treated as described above, was ovariectomized under pentobarbital anesthesia at 10 weeks of age. At 15-17 weeks of age, half of each group received a subcutaneous injection of 5 μg estradiol benzoate a day before the passive avoidance learning test. Passive avoidance learning behavior was impaired by the 0.02 mg/kg EE dose, but notably only in the estradiol benzoate-injected group. At 17-19 weeks of age, hippocampal and cortical samples were collected from rats with or without the 5 μg estradiol benzoate injection, and western blots used to determine ERα expression. A significant decrease in ERα expression was observed in the hippocampus of the estradiol-injected, neonatal EE-treated females. The results demonstrated that exposure to EE immediately after birth decreased learning ability in adult female rats, and that this may be at least partly mediated by the decreased expression of ERα in the hippocampus.

  8. A Single Neonatal Injection of Ethinyl Estradiol Impairs Passive Avoidance Learning and Reduces Expression of Estrogen Receptor α in the Hippocampus and Cortex of Adult Female Rats

    PubMed Central

    Shiga, Tatsuomi; Nakamura, Takahiro J.; Komine, Chiaki; Goto, Yoshikuni; Mizoguchi, Yasushi; Yoshida, Midori; Kondo, Yasuhiko; Kawaguchi, Maiko

    2016-01-01

    Although perinatal exposure of female rats to estrogenic compounds produces irreversible changes in brain function, it is still unclear how the amount and timing of exposure to those substances affect learning function, or if exposure alters estrogen receptor α (ERα) expression in the hippocampus and cortex. In adult female rats, we investigated the effects of neonatal exposure to a model estrogenic compound, ethinyl estradiol (EE), on passive avoidance learning and ERα expression. Female Wistar-Imamichi rats were subcutaneously injected with oil, 0.02 mg/kg EE, 2 mg/kg EE, or 20 mg/kg 17β-estradiol within 24 h after birth. All females were tested for passive avoidance learning at the age of 6 weeks. Neonatal 0.02 mg/kg EE administration significantly disrupted passive avoidance compared with oil treatment in gonadally intact females. In a second experiment, another set of experimental females, treated as described above, was ovariectomized under pentobarbital anesthesia at 10 weeks of age. At 15–17 weeks of age, half of each group received a subcutaneous injection of 5 μg estradiol benzoate a day before the passive avoidance learning test. Passive avoidance learning behavior was impaired by the 0.02 mg/kg EE dose, but notably only in the estradiol benzoate-injected group. At 17–19 weeks of age, hippocampal and cortical samples were collected from rats with or without the 5 μg estradiol benzoate injection, and western blots used to determine ERα expression. A significant decrease in ERα expression was observed in the hippocampus of the estradiol-injected, neonatal EE-treated females. The results demonstrated that exposure to EE immediately after birth decreased learning ability in adult female rats, and that this may be at least partly mediated by the decreased expression of ERα in the hippocampus. PMID:26741502

  9. Ovariectomy-Induced Mitochondrial Oxidative Stress, Apoptosis, and Calcium Ion Influx Through TRPA1, TRPM2, and TRPV1 Are Prevented by 17β-Estradiol, Tamoxifen, and Raloxifene in the Hippocampus and Dorsal Root Ganglion of Rats.

    PubMed

    Yazğan, Yener; Nazıroğlu, Mustafa

    2016-11-10

    Relative 17β-estradiol (E2) deprivation and excessive production of mitochondrial oxygen free radicals (OFRs) with a high amount of Ca(2+) influx TRPA1, TRPM2, and TRPV1 activity is one of the main causes of neurodegenerative disease in postmenopausal women. In addition to the roles of tamoxifen (TMX) and raloxifene (RLX) in cancer and bone loss treatments, regulator roles in Ca(2+) influx and mitochondrial oxidative stress in neurons have not been reported. The aim of this study was to evaluate whether TMX and RLX interactions with TRPA1, TRPM2, and TRPV1 in primary hippocampal (HPC) and dorsal root ganglion (DRG) neuron cultures of ovariectomized (OVX) rats. Forty female rats were divided into five groups: a control group, an OVX group, an OVX+E2 group, an OVX+TMX group, and an OVX+RLX group. The OVX+E2, OVX+TMX, and OVX+RLX groups received E2, TMX, and RLX, respectively, for 14 days after the ovariectomy. E2, ovariectomy-induced TRPA1, TRPM2, and TRPV1 current densities, as well as accumulation of cytosolic free Ca(2+) in the neurons, were returned to the control levels by E2, TMX, and RLX treatments. In addition, E2, TMX, and RLX via modulation of TRPM2 and TRPV1 activity reduced ovariectomy-induced mitochondrial membrane depolarization, apoptosis, and cytosolic OFR production. TRPM2, TRPV1, PARP, and caspase-3 and caspase-9 expressions were also decreased in the neurons by the E2, TMX, and RLX treatments. In conclusion, we first reported the molecular effects of E2, TMX, and RLX on TRPA1, TRPM2, and TRPV1 channel activation in the OVX rats. In addition, we observed neuroprotective effects of E2, RLX, and TMX on oxidative and apoptotic injuries of the hippocampus and peripheral pain sensory neurons (DRGs) in the OVX rats. Graphical Abstract Possible molecular pathways of involvement of DEX in cerebral ischemia-induced apoptosis, oxidative stress, and calcium accumulation through TRPA1, TRPM2 and TRPV1 in the hippocampus and DRG neurons of rats. The N domain

  10. Modulation of Diabetes-Induced Oxidative Stress, Apoptosis, and Ca(2+) Entry Through TRPM2 and TRPV1 Channels in Dorsal Root Ganglion and Hippocampus of Diabetic Rats by Melatonin and Selenium.

    PubMed

    Kahya, Mehmet Cemal; Nazıroğlu, Mustafa; Övey, İshak Suat

    2017-04-01

    Neuropathic pain and hippocampal injury can arise from the overload of diabetes-induced calcium ion (Ca(2+)) entry and oxidative stress. The transient receptor potential (TRP) melastatin 2 (TRPM2) and TRP vanilloid type 1 (TRPV1) are expressed in sensory neurons and hippocampus. Moreover, activations of TRPM2 and TRPV1 during oxidative stress have been linked to neuronal death. Melatonin (MEL) and selenium (Se) have been considered potent antioxidants that detoxify a variety of reactive oxygen species (ROS) in neurological diseases. In order to better characterize the actions of MEL and Se in diabetes-induced peripheral pain and hippocampal injury through modulation of TRPM2 and TRPV1, we tested the effects of MEL and Se on apoptosis and oxidative stress in the hippocampal and dorsal root ganglion (DRG) neurons of streptozotocin (STZ)-induced diabetic rats. Fifty-eight rats were divided into six groups. The first group was used as control. The second group was used as the diabetic group. The third and fourth groups received Se and MEL, respectively. Intraperitoneal Se and MEL were given to diabetic rats in the fifth and sixth groups. On the 14th day, hippocampal and DRG neuron samples were freshly taken from all animals. The neurons were stimulated with a TRPV1 channel agonist (capsaicin) and a TRPM2 channel agonist (cumene hydroperoxide). We observed a modulator role of MEL and Se on intracellular free Ca(2+) concentrations, current densities of TRPM2 and TRPV1 channels, apoptosis, caspase 3, caspase 9, mitochondrial depolarization, reduced glutathione, glutathione peroxidase, lipid peroxidation, and intracellular ROS production values in the neurons. In addition, procaspase 3 and 9 activities in western blot analyses of the brain cortex were also decreased by MEL and Se treatments. In conclusion, in our diabetes experimental model, TRPM2 and TRPV1 channels are involved in the Ca(2+) entry-induced neuronal death and modulation of this channel activity by MEL and

  11. PTU-induced hypothyroidism in rats leads to several early neuropathological signs of Alzheimer's disease in the hippocampus and spatial memory impairments.

    PubMed

    Chaalal, Amina; Poirier, Roseline; Blum, David; Gillet, Brigitte; Le Blanc, Pascale; Basquin, Marie; Buée, Luc; Laroche, Serge; Enderlin, Valérie

    2014-11-01

    The multifactorial causes impacting the risk of developing sporadic forms of Alzheimer's disease (AD) remain to date poorly understood. Epidemiologic studies in humans and research in rodents have suggested that hypothyroidism could participate in the etiology of AD. Recently, we reported that adult-onset hypothyroidism in rats favors β-amyloid peptide production in the hippocampus. Here, using the same hypothyroidism model with the antithyroid molecule propythiouracyl (PTU), we further explored AD-related features, dysfunctional cell-signaling mechanisms and hippocampal-dependent learning and memory. In vivo MRI revealed a progressive decrease in cerebral volume of PTU-treated rats. In the hippocampus, hypothyroidism resulted in tau hyperphosphorylation and increases in several proinflammatory cytokines. These modifications were associated with impaired spatial memory and reduced hippocampal expression of signaling molecules important for synaptic plasticity and memory, including neurogranin, CaMKII, ERK, GSK3β, CREB, and expression of the transcription factor EGR1/Zif268. These data strengthen the idea that hypothyroidism represents an important factor influencing the risk of developing sporadic forms of AD. Copyright © 2014 Wiley Periodicals, Inc.

  12. Resveratrol Attenuates Subacute Systemic Inflammation-Induced Spatial Memory Impairment via Inhibition of Astrocyte Activation and Enhancement of Synaptophysin Expression in the Hippocampus.

    PubMed

    Chen, Ying-Ying; Zhang, Li; Shi, Dong-Ling; Song, Xing-Hui; Shen, Yue-Liang; Zheng, Ming-Zhi; Wang, Lin-Lin

    2017-01-01

    The aim of this study was to investigate the role of resveratrol on subacute systemic inflammation-induced dysfunction of cognitive memory in mice and its underlying mechanism. Male ICR mice were trained in a water maze for four days of acquisition training and one day of probe trial. Subacute treatment with lipopolysaccharide (LPS) (1 mg/kg) by intraperitoneal injection for 5 days was used to establish a systemic inflammatory model. All mice were sacrificed after probe testing, then the expression of glial fibrillary acidic protein (GFAP), synaptophysin, and sirtuin1 (SIRT1) in hippocampi were determined using immunohistochemistry or western blot analysis. Morris water maze tests indicated that hippocampus-dependent spatial learning and memory were impaired in LPS-treated group. Resveratrol attenuated LPS-induced memory deficit in dose-dependent manner. Immunohistochemistry and western blot analysis revealed that LPS increased hippocampal GFAP expression and inhibited synaptophysin expression, which were prevented by resveratrol treatment. Treatment with LPS declined the SIRT1 protein expression in the hippocampus, which could be prevented by resveratrol. The protective effect of resveratrol could be abolished by a specific SIRT1 inhibitor. Our findings add new experimental data for potential therapeutic effects of resveratrol in the brain in a model of subacute systemic inflammation-induced astrocyte activation, synaptic alteration and cognitive decline. © 2017 by the Association of Clinical Scientists, Inc.

  13. Rescue of Cyclic AMP Mediated Long Term Potentiation Impairment in the Hippocampus of Mecp2 Knockout (Mecp2(-/y) ) Mice by Rolipram.

    PubMed

    Balakrishnan, Saju; Niebert, Marcus; Richter, Diethelm W

    2016-01-01

    Rett syndrome (RTT) patients experience learning difficulties and memory loss. Analogous deficits of hippocampal plasticity are reported in mouse models of RTT. To elucidate the underlying pathophysiology, we studied long term potentiation (LTP) at the CA3 to CA1 synapses in the hippocampus in acute brain slices from WT and Mecp2(-/y) mice, by either activating cAMP dependent pathway or using high frequency stimulation, by means of patch clamp. We have observed that, the NMDA channel current characteristics remain unchanged in the Mecp2(-/y) mice. The adenylyl cyclase (AC) agonist forskolin evoked a long lasting potentiation of evoked EPSCs in WT CA1 neurons, but only minimally enhanced the EPSCs in the Mecp2(-/y) mice. This weaker potentiation in Mecp2 (-/) (y) mice was ameliorated by application of phosphodiesterase 4 inhibitor rolipram. The hyperpolarization activated cyclic nucleotide gated channel current (I h) was potentiated to similar extent by forskolin in both phenotypes. Multiple tetanus induced cAMP-dependent plasticity was also impaired in the Mecp2 (-/) (y) mice, and was also partially rescued by rolipram. Western blot analysis of CA region of Mecp2 (-/) (y) mice hippocampus revealed more than twofold up-regulation of protein kinase A (PKA) regulatory subunits, while the expression of the catalytic subunit remained unchanged. We hypothesize that the overexpressed PKA regulatory subunits buffer cAMP and restrict the PKA mediated phosphorylation of target proteins necessary for LTP. Blocking the degradation of cAMP, thereby saturating the regulatory subunits alleviated this defect.

  14. The plasma membrane redox system is impaired by amyloid β-peptide and in the hippocampus and cerebral cortex of 3xTgAD mice.

    PubMed

    Hyun, Dong-Hoon; Mughal, Mohamed R; Yang, Hyunwon; Lee, Ji Hyun; Ko, Eun Joo; Hunt, Nicole D; de Cabo, Rafael; Mattson, Mark P

    2010-10-01

    Membrane-associated oxidative stress has been implicated in the synaptic dysfunction and neuronal degeneration that occurs in Alzheimer's disease (AD), but the underlying mechanisms are unknown. Enzymes of the plasma membrane redox system (PMRS) provide electrons for energy metabolism and recycling of antioxidants. Here, we show that activities of several PMRS enzymes are selectively decreased in plasma membranes from the hippocampus and cerebral cortex of 3xTgAD mice, an animal model of AD. Our results that indicate the decreased PMRS enzyme activities are associated with decreased levels of coenzyme Q(10) and increased levels of oxidative stress markers. Neurons overexpressing the PMRS enzymes (NQO1 or cytochrome b5 reductase) exhibit increased resistance to amyloid β-peptide (Aβ). If and to what extent Aβ is the cause of the impaired PMRS enzymes in the 3xTgAD mice is unknown. Because these mice also express mutant tau and presenilin-1, it is possible that one or more of the PMRS could be adversely affected by these mutations. Nevertheless, the results of our cell culture studies clearly show that exposure of neurons to Aβ1-42 is sufficient to impair PMRS enzymes. The impairment of the PMRS in an animal model of AD, and the ability of PMRS enzyme activities to protect neurons against Aβ-toxicity, suggest enhancement PMRS function as a novel approach for protecting neurons against oxidative damage in AD and related disorders. Copyright © 2010 Elsevier Inc. All rights reserved.

  15. Isoflurane anesthesia promotes cognitive impairment by inducing expression of β-amyloid protein-related factors in the hippocampus of aged rats.

    PubMed

    Zhang, Shuai; Hu, Xueyuan; Guan, Wei; Luan, Li; Li, Bei; Tang, Qichao; Fan, Honggang

    2017-01-01

    Isoflurane anesthesia has been shown to be responsible for cognitive impairment in Alzheimer's disease (AD) and development of AD in the older age groups. However, the pathogenesis of AD-related cognitive impairments induced by isoflurane anesthesia remains elusive. Thus, this study was designed to investigate the mechanism by which isoflurane anesthesia caused AD-related cognitive impairments. Aged Wistar rats were randomly divided into 6 groups (n = 12), 1 control group (CONT) and 5 isoflurane treated (ISO) groups (ISO 0, ISO 0.5D, ISO 1D, ISO 3D and ISO 7D). The CONT group inhaled 30% O2 for 2 h without any anesthesia. ISO groups were placed under anesthesia with 3% isoflurane and then exposed to 1.5% isoflurane delivered in 30% O2 for 2 h. Rats in each ISO group were then analyzed immediately (ISO 0) or at various time points (0.5, 1, 3 or 7 day) after this exposure. Cognitive function was assessed using the Morris water maze test. Protein levels of amyloid precursor protein (APP), β-site APP cleavage enzyme-1 (BACE-1) and Aβ42 peptide were analyzed in hippocampal samples by Western blot. β-Amyloid (Abeta) plaques were detected in hippocampal sections by Congo red staining. Compared with controls, all ISO groups showed increased escape latency and impaired spatial memory. Isoflurane increased APP mRNA expression and APP protein depletion, promoting Aβ42 overproduction, oligomerization and accumulation. However, isoflurane did not affect BACE-1 expression. Abeta plaques were observed only in those ISO groups sacrificed at 3 or 7 d. Our data indicate that aged rats exposed to isoflurane had increased APP mRNA expression and APP protein depletion, with Aβ42 peptide overproduction and oligomerization, resulting in formation of Abeta plaques in the hippocampus. Such effects might have contributed to cognitive impairments, including in spatial memory, observed in these rats after isoflurane anesthesia.

  16. Music application alleviates short-term memory impairments through increasing cell proliferation in the hippocampus of valproic acid-induced autistic rat pups.

    PubMed

    Lee, Sung-Min; Kim, Bo-Kyun; Kim, Tae-Woon; Ji, Eun-Sang; Choi, Hyun-Hee

    2016-06-01

    Autism is a neurodevelopmental disorder and this disorder shows impairment in reciprocal social interactions, deficits in communication, and restrictive and repetitive patterns of behaviors and interests. The effect of music on short-term memory in the view of cell proliferation in the hippocampus was evaluated using valproic acid-induced autistic rat pups. Animal model of autism was made by subcutaneous injection of 400-mg/kg valproic acid into the rat pups on the postnatal day 14. The rat pups in the music-applied groups were exposed to the 65-dB comfortable classic music for 1 hr once a day, starting postnatal day 15 and continued until postnatal day 28. In the present results, short-term memory was deteriorated by autism induction. The numbers of 5-bromo-2'-deoxyridine (BrdU)-positive, Ki-67-positive, and doublecortin (DCX)-positive cells in the hippocampal dentate gyrus were decreased by autism induction. Brain-derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB) expressions in the hippocampus were also suppressed in the autistic rat pups. Music application alleviated short-term memory deficits with enhancing the numbers of BrdU-positive, Ki-67-positive, and DCX-positive cells in the autistic rat pups. Music application also enhanced BDNF and TrkB expressions in the autistic rat pups. The present study show that application of music enhanced hippocampal cell proliferation and alleviated short-term memory impairment through stimulating BDNF-TrkB signaling in the autistic rat pups. Music can be suggested as the therapeutic strategy to overcome the autism-induced memory deficits.

  17. Music application alleviates short-term memory impairments through increasing cell proliferation in the hippocampus of valproic acid-induced autistic rat pups

    PubMed Central

    Lee, Sung-Min; Kim, Bo-Kyun; Kim, Tae-Woon; Ji, Eun-Sang; Choi, Hyun-Hee

    2016-01-01

    Autism is a neurodevelopmental disorder and this disorder shows impairment in reciprocal social interactions, deficits in communication, and restrictive and repetitive patterns of behaviors and interests. The effect of music on short-term memory in the view of cell proliferation in the hippocampus was evaluated using valproic acid-induced autistic rat pups. Animal model of autism was made by subcutaneous injection of 400-mg/kg valproic acid into the rat pups on the postnatal day 14. The rat pups in the music-applied groups were exposed to the 65-dB comfortable classic music for 1 hr once a day, starting postnatal day 15 and continued until postnatal day 28. In the present results, short-term memory was deteriorated by autism induction. The numbers of 5-bromo-2′-deoxyridine (BrdU)-positive, Ki-67-positive, and doublecortin (DCX)-positive cells in the hippocampal dentate gyrus were decreased by autism induction. Brain-derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB) expressions in the hippocampus were also suppressed in the autistic rat pups. Music application alleviated short-term memory deficits with enhancing the numbers of BrdU-positive, Ki-67-positive, and DCX-positive cells in the autistic rat pups. Music application also enhanced BDNF and TrkB expressions in the autistic rat pups. The present study show that application of music enhanced hippocampal cell proliferation and alleviated short-term memory impairment through stimulating BDNF-TrkB signaling in the autistic rat pups. Music can be suggested as the therapeutic strategy to overcome the autism-induced memory deficits. PMID:27419108

  18. Acute and chronic interference with BDNF/TrkB-signaling impair LTP selectively at mossy fiber synapses in the CA3 region of mouse hippocampus.

    PubMed

    Schildt, Sandra; Endres, Thomas; Lessmann, Volkmar; Edelmann, Elke

    2013-08-01

    Brain-derived neurotrophic factor (BDNF) signaling via TrkB crucially regulates synaptic plasticity in the brain. Although BDNF is abundant at hippocampal mossy fiber (MF) synapses, which critically contribute to hippocampus dependent memory, its role in MF synaptic plasticity (long-term potentiation, LTP) remained largely unclear. Using field potential recordings in CA3 of adult heterozygous BDNF knockout (ko, BDNF+/-) mice we observed impaired (∼50%) NMDAR-independent MF-LTP. In contrast to MF synapses, LTP at neighboring associative/commissural (A/C) fiber synapses remained unaffected. To exclude that impaired MF-LTP in BDNF+/- mice was due to developmental changes in response to chronically reduced BDNF levels, and to prove the importance of acute availability of BDNF in MF-LTP, we also tested effects of acute interference with BDNF/TrkB signaling. Inhibition of TrkB tyrosine kinase signaling with k252a, or with the selective BDNF scavenger TrkB-Fc, both inhibited MF-LTP to the same extent as observed in BDNF+/- mice. Basal synaptic transmission, short-term plasticity, and synaptic fatigue during LTP induction were not significantly altered by treatment with k252a or TrkB-Fc, or by chronic BDNF reduction in BDNF+/- mice. Since the acute interference with BDNF-signaling did not completely block MF-LTP, our results provide evidence that an additional mechanism besides BDNF induced TrkB signaling contributes to this type of LTP. Our results prove for the first time a mechanistic action of acute BDNF/TrkB signaling in presynaptic expression of MF-LTP in adult hippocampus.

  19. GESTATIONAL AND LACTATIONAL EXPOSURE TO PROPYLTHIOURACIL INDUCES HYPOTHYROIDISM AND IMPAIRS SYNAPTIC TRANSMISSION AND PLASTICITY IN AREA CA1 OF HIPPOCAMPUS.

    EPA Science Inventory

    Although severe developmental hypothyroidism leads to stunted growth, alterations in hippocampal structure, and impaired performance on a variety of behavioral learning tasks, the impact of milder forms of hypothyroidism has not been adequately assessed. Preliminary reports of ...

  20. GESTATIONAL AND LACTATIONAL EXPOSURE TO PROPYLTHIOURACIL INDUCES HYPOTHYROIDISM AND IMPAIRS SYNAPTIC TRANSMISSION AND PLASTICITY IN AREA CA1 OF HIPPOCAMPUS.

    EPA Science Inventory

    Although severe developmental hypothyroidism leads to stunted growth, alterations in hippocampal structure, and impaired performance on a variety of behavioral learning tasks, the impact of milder forms of hypothyroidism has not been adequately assessed. Preliminary reports of ...

  1. Rapamycin inhibits mTOR/p70S6K activation in CA3 region of the hippocampus of the rat and impairs long term memory.

    PubMed

    Lana, D; Di Russo, J; Mello, T; Wenk, G L; Giovannini, M G

    2017-01-01

    The present study was aimed at establishing whether the mTOR pathway and its downstream effector p70S6K in CA3 pyramidal neurons are under the modulation of the cholinergic input to trigger the formation of long term memories, similar to what we demonstrated in CA1 hippocampus. We performed in vivo behavioral experiments using the step down inhibitory avoidance test in adult Wistar rats to evaluate memory formation under different conditions. We examined the effects of rapamycin, an inhibitor of mTORC1 formation, scopolamine, a muscarinic receptor antagonist or mecamylamine, a nicotinic receptor antagonist, on short and long term memory formation and on the functionality of the mTOR pathway. Acquisition was conducted 30min after i.c.v. injection of rapamycin. Recall testing was performed 1h, 4h or 24h after acquisition. We found that (1) mTOR and p70S6K activation in CA3 pyramidal neurons were involved in long term memory formation; (2) rapamycin significantly inhibited mTOR and of p70S6K activation at 4h, and long term memory impairment 24h after acquisition; (3) scopolamine impaired short but not long term memory, with an early increase of mTOR/p70S6K activation at 1h followed by stabilization at longer times; (4) mecamylamine and scopolamine co-administration impaired short term memory at 1h and 4h and reduced the scopolamine-induced increase of mTOR/p70S6K activation at 1h and 4h; (5) mecamylamine and scopolamine treatment did not impair long term memory formation; (6) unexpectedly, rapamycin increased mTORC2 activation in microglial cells. Our results demonstrate that in CA3 pyramidal neurons the mTOR/p70S6K pathway is under the modulation of the cholinergic system and is involved in long-term memory encoding, and are consistent with the hypothesis that the CA3 region of the hippocampus is involved in memory mechanisms based on rapid, one-trial object-place learning and recall. Furthermore, our results are in accordance with previous reports that selective

  2. Delayed Administration of Alpha-Difluoromethylornithine Prevents Hippocampus-Dependent Cognitive Impairment after Single and Combined Injury in Mice

    PubMed Central

    Allen, Antiño R.; Eilertson, Kirsten; Sharma, Sourabh; Baure, Jennifer; Allen, Barrett; Leu, David; Rosi, Susanna; Raber, Jacob; Huang, Ting-Ting; Fike, John R.

    2014-01-01

    Radiation exposure due to radiological terrorism and military circumstances are a continuing threat for the civilian population. In an uncontrolled radiation event, it is likely that there will be other types of injury involved, including trauma. While radiation combined injury is recognized as an area of great significance, overall there is a paucity of information regarding the mechanisms underlying the interactions between irradiation and other forms of injury, or what countermeasures might be effective in ameliorating such changes. The objective of this study was to determine if difluoromethylornithine (DFMO) could reduce the adverse effects of single or combined injury if administered beginning 24 h after exposure. Eight-week-old C57BL/J6 young-adult male mice received whole-body cesium-137 (137Cs) irradiation with 4 Gy. Immediately after irradiation, unilateral traumatic brain injury was induced using a controlled cortical impact system. Forty-four days postirradiation, animals were tested for hippocampus-dependent cognitive performance in the Morris water maze. After cognitive testing, animals were euthanized and their brains snap frozen for immunohisto-chemical assessment of neuroinflammation (activated microglia) and neurogenesis in the hippocampal dentate gyrus. Our data show that single and combined injuries induced variable degrees of hippocampus-dependent cognitive dysfunction, and when given 24 h post trauma, DFMO treatment ameliorated those effects. Cellular changes including neuro-genesis and numbers of activated microglia were generally not associated with the cognitive changes. Further analyses also revealed that DFMO increased hippocampal protein levels of the antioxidants thioredoxin 1 and peroxiredoxin 3 compared to vehicle treated animals. While the mechanisms responsible for the improvement in cognition after DFMO treatment are not yet clear, these results constitute a basis for further development of DFMO as a countermeasure for ameliorating

  3. Postnatal treadmill exercise alleviates short-term memory impairment by enhancing cell proliferation and suppressing apoptosis in the hippocampus of rat pups born to diabetic rats.

    PubMed

    Kim, Young Hoon; Sung, Yun-Hee; Lee, Hee-Hyuk; Ko, Il-Gyu; Kim, Sung-Eun; Shin, Mal-Soon; Kim, Bo-Kyun

    2014-08-01

    During pregnancy, diabetes mellitus exerts detrimental effects on the development of the fetus, especially the central nervous system. In the current study, we evaluated the effects of postnatal treadmill exercise on short-term memory in relation with cell proliferation and apoptosis in the hippocampus of rat pups born to streptozotocin (STZ)-induced diabetic maternal rats. Adult female rats were mated with male rats for 24 h. Two weeks after mating, the pregnant female rats were divided into two groups: control group and STZ injection group. The pregnant rats in the STZ injection group were administered 40 mg/kg of STZ intraperitoneally. After birth, the rat pups were divided into the following four groups: control group, control with postnatal exercise group, maternal STZ-injection group, and maternal STZ-injection with postnatal exercise group. The rat pups in the postnatal exercise groups were made to run on a treadmill for 30 min once a day, 5 times per week for 2 weeks beginning 4 weeks after birth. The rat pups born to diabetic rats were shown to have short-term memory impairment with suppressed cell proliferation and increased apoptosis in the hippocampal dentate gyrus. Postnatal treadmill exercise alleviated short-term memory impairment by increased cell proliferation and suppressed apoptosis in the rat pups born to diabetic rats. These findings indicate that postnatal treadmill exercise may be used as a valuable strategy to ameliorate neurodevelopmental problems in children born to diabetics.

  4. Lithium chloride administration prevents spatial learning and memory impairment in repeated cerebral ischemia-reperfusion mice by depressing apoptosis and increasing BDNF expression in hippocampus.

    PubMed

    Fan, Mingyue; Jin, Wei; Zhao, Haifeng; Xiao, Yining; Jia, Yanqiu; Yin, Yu; Jiang, Xin; Xu, Jing; Meng, Nan; Lv, Peiyuan

    2015-09-15

    Lithium has been reported to have neuroprotective effects, but the preventive and treated role on cognition impairment and the underlying mechanisms have not been determined. In the present study, C57Bl/6 mice were subjected to repeated bilateral common carotid artery occlusion to induce the learning and memory deficits. 2 mmol/kg or 5 mmol/kg of lithium chloride (LiCl) was injected intraperitoneally per day before (for 7 days) or post (for 28 days) the operation. This repeated cerebral ischemia-reperfusion (IR) induced dynamic overexpression of ratio of Bcl-2/Bax and BDNF in hippocampus of mice. LiCl pretreatment and treatment significantly decreased the escape latency and increased the percentage of time that the mice spent in the target quadrant in Morris water maze. 2 mmol/kg LiCl evidently reversed the morphologic changes, up-regulated the survival neuron count and increased the BDNF gene and protein expression. 5 mmol/kg pre-LiCl significantly increased IR-stimulated reduce of Bcl-2/Bax and p-CREB/CREB. These results described suggest that pre-Li and Li treatment may induce a pronounced prevention on cognitive impairment. These effects may relay on the inhibition of apoptosis and increasing BDNF and p-CREB expression.

  5. Aberrant Location of Inhibitory Synaptic Marker Proteins in the Hippocampus of Dystrophin-Deficient Mice: Implications for Cognitive Impairment in Duchenne Muscular Dystrophy

    PubMed Central

    Krasowska, Elżbieta; Zabłocki, Krzysztof; Górecki, Dariusz C.; Swinny, Jerome D.

    2014-01-01

    Duchenne muscular dystrophy (DMD) is a neuromuscular disease that arises from mutations in the dystrophin-encoding gene. Apart from muscle pathology, cognitive impairment, primarily of developmental origin, is also a significant component of the disorder. Convergent lines of evidence point to an important role for dystrophin in regulating the molecular machinery of central synapses. The clustering of neurotransmitter receptors at inhibitory synapses, thus impacting on synaptic transmission, is of particular significance. However, less is known about the role of dystrophin in influencing the precise expression patterns of proteins located within the pre- and postsynaptic elements of inhibitory synapses. To this end, we exploited molecular markers of inhibitory synapses, interneurons and dystrophin-deficient mouse models to explore the role of dystrophin in determining the stereotypical patterning of inhibitory connectivity within the cellular networks of the hippocampus CA1 region. In tissue from wild-type (WT) mice, immunoreactivity of neuroligin2 (NL2), an adhesion molecule expressed exclusively in postsynaptic elements of inhibitory synapses, and the vesicular GABA transporter (VGAT), a marker of GABAergic presynaptic elements, were predictably enriched in strata pyramidale and lacunosum moleculare. In acute contrast, NL2 and VGAT immunoreactivity was relatively evenly distributed across all CA1 layers in dystrophin-deficient mice. Similar changes were evident with the cannabinoid receptor 1, vesicular glutamate transporter 3, parvalbumin, somatostatin and the GABAA receptor alpha1 subunit. The data show that in the absence of dystrophin, there is a rearrangement of the molecular machinery, which underlies the precise spatio-temporal pattern of GABAergic synaptic transmission within the CA1 sub-field of the hippocampus. PMID:25260053

  6. Rescue of Cyclic AMP Mediated Long Term Potentiation Impairment in the Hippocampus of Mecp2 Knockout (Mecp2-/y) Mice by Rolipram

    PubMed Central

    Balakrishnan, Saju; Niebert, Marcus; Richter, Diethelm W.

    2016-01-01

    Rett syndrome (RTT) patients experience learning difficulties and memory loss. Analogous deficits of hippocampal plasticity are reported in mouse models of RTT. To elucidate the underlying pathophysiology, we studied long term potentiation (LTP) at the CA3 to CA1 synapses in the hippocampus in acute brain slices from WT and Mecp2-/y mice, by either activating cAMP dependent pathway or using high frequency stimulation, by means of patch clamp. We have observed that, the NMDA channel current characteristics remain unchanged in the Mecp2-/y mice. The adenylyl cyclase (AC) agonist forskolin evoked a long lasting potentiation of evoked EPSCs in WT CA1 neurons, but only minimally enhanced the EPSCs in the Mecp2-/y mice. This weaker potentiation in Mecp2-/y mice was ameliorated by application of phosphodiesterase 4 inhibitor rolipram. The hyperpolarization activated cyclic nucleotide gated channel current (Ih) was potentiated to similar extent by forskolin in both phenotypes. Multiple tetanus induced cAMP-dependent plasticity was also impaired in the Mecp2-/y mice, and was also partially rescued by rolipram. Western blot analysis of CA region of Mecp2-/y mice hippocampus revealed more than twofold up-regulation of protein kinase A (PKA) regulatory subunits, while the expression of the catalytic subunit remained unchanged. We hypothesize that the overexpressed PKA regulatory subunits buffer cAMP and restrict the PKA mediated phosphorylation of target proteins necessary for LTP. Blocking the degradation of cAMP, thereby saturating the regulatory subunits alleviated this defect. PMID:26869885

  7. Impaired expression of GABA transporters in the human Alzheimer's disease hippocampus, subiculum, entorhinal cortex and superior temporal gyrus.

    PubMed

    Fuhrer, Tessa E; Palpagama, Thulani H; Waldvogel, Henry J; Synek, Beth J L; Turner, Clinton; Faull, Richard L; Kwakowsky, Andrea

    2017-05-20

    Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain and plays an important role in regulating neuronal excitability. GABA reuptake from the synapse is dependent on specific transporters - mainly GAT-1, GAT-3 and BGT-1 (GATs). This study is the first to show alterations in the expression of the GATs in the Alzheimer's disease (AD) hippocampus, entorhinal cortex and superior temporal gyrus. We found a significant increase in BGT-1 expression associated with AD in all layers of the dentate gyrus, in the stratum oriens of the CA2 and CA3 and the superior temporal gyrus. In AD there was a significant decrease in GAT-1 expression in the entorhinal cortex and superior temporal gyrus. We also found a significant decrease in GAT-3 immunoreactivity in the stratum pyramidale of the CA1 and CA3, the subiculum and entorhinal cortex. These observations indicate that the expression of the GATs shows brain-region- and layer-specific alterations in AD, suggesting a complex activation pattern of different GATs during the course of the disease. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

  8. Acupuncture ameliorates cognitive impairment and hippocampus neuronal loss in experimental vascular dementia through Nrf2-mediated antioxidant response.

    PubMed

    Wang, Xue-Rui; Shi, Guang-Xia; Yang, Jing-Wen; Yan, Chao-Qun; Lin, Li-Ting; Du, Si-Qi; Zhu, Wen; He, Tian; Zeng, Xiang-Hong; Xu, Qian; Liu, Cun-Zhi

    2015-12-01

    Emerging evidence suggests acupuncture could exert neuroprotection in the vascular dementia via anti-oxidative effects. However, the involvement of Nrf2, a master regulator of antioxidant defense, in acupuncture-induced neuroprotection in vascular dementia remains undetermined. The goal of our study was to investigate the contribution of Nrf2 in acupuncture and its effects on vascular dementia. Morris water maze and Nissl staining were used to assess the effect of acupuncture on cognitive function and hippocampal neurodegeneration in experimental vascular dementia. The distribution of Nrf2 in neurons in hippocampus, the protein expression of Nrf2 in both cytosol and nucleus, and the protein and mRNA levels of its downstream target genes NQO1 and HO-1 were detected by double immunofluorescent staining, Western blotting and realtime PCR analysis respectively. Cognitive function and microglia activation were measured in both wild-type and Nrf2 gene knockout mice after acupuncture treatment. We found that acupuncture could remarkably reverse the cognitive deficits, neuron cell loss, reactive oxygen species production, and decreased cerebral blood flow. It was notable that acupuncture enhanced nuclear translocation of Nrf2 in neurons and up-regulate the protein and mRNA levels of Nrf2 and its target genes HO-1 and NQO1. Moreover, acupuncture could significantly down-regulated the over-activation of microglia after common carotid artery occlusion surgery. However, the reversed cognitive deficits, neuron cell loss and microglia activation by acupuncture were abolished in Nrf2 gene knockout mice. In conclusion, these findings provide evidence that the neuroprotection of acupuncture in models of vascular dementia was via the Nrf2 activation and Nrf2-dependent microglia activation. Copyright © 2015. Published by Elsevier Inc.

  9. Propofol Mitigates Learning and Memory Impairment After Electroconvulsive Shock in Depressed Rats by Inhibiting Autophagy in the Hippocampus

    PubMed Central

    Li, Ping; Hao, Xue-chao; Luo, Jie; Lv, Feng; Wei, Ke; Min, Su

    2016-01-01

    Background The present study explored the effects of propofol on hippocampal autophagy and synaptophysin in depression-model rats undergoing electroconvulsive shock (ECS). Material/Methods The rat depression model was established by exposing Sprague-Dawley rats to stress for 28 consecutive days. Forty rats were assigned randomly into the depression group (group D; no treatment), the ECS group (group E), the propofol group (group P), and the propofol + ECS group (group PE). Open field tests and sucrose preference tests were applied to evaluate the depression behavior; and Morris water maze tests were used to assess the learning and memory function of the rats. Western blotting was used to detect the expression of Beclin-1 and LC3-II/I; and ELISA was applied to assess the expression of synaptophysin. Results Rats in group E and group PE scored higher in the open field and sucrose preference tests compared with those in group D. Furthermore, rats in group E also had a longer escape latency, a shorter space exploration time, and increased expression of Beclin-1, LC3-II/I, and synaptophysin. Compared with group E, rats in group PE possessed a shorter escape latency, a longer space exploration time, reduced expression of Beclin-1, LC3-II/I, and synaptophysin. Conclusions Propofol could inhibit excessive ECS-induced autophagy and synaptophysin overexpression in the hippocampus, thus protecting the learning and memory functions in depressed rats after ECS. The inhibitory effects of propofol on the overexpression of synaptophysin may result from its inhibitory effects on the excessive induction of autophagy. PMID:27203836

  10. Impairment of object recognition memory by maternal bisphenol A exposure is associated with inhibition of Akt and ERK/CREB/BDNF pathway in the male offspring hippocampus.

    PubMed

    Wang, Chong; Li, Zhihui; Han, Haijun; Luo, Guangying; Zhou, Bingrui; Wang, Shaolin; Wang, Jundong

    2016-02-03

    Bisphenol A (BPA) is a commonly used endocrine-disrupting chemical used as a component of polycarbonates plastics that has potential adverse effects on human health. Exposure to BPA during development has been implicated in memory deficits, but the mechanism of action underlying the effect is not fully understood. In this study, we investigated the effect of maternal exposure to BPA on object recognition memory and the expressions of proteins important for memory, especially focusing on the ERK/CREB/BDNF pathway. Pregnant Sprague-Dawley female rats were orally treated with either vehicle or BPA (0.05, 0.5, 5 or 50 mg/kg BW/day) during days 9-20 of gestation. Male offspring were tested on postnatal day 21 with the object recognition task. Recognition memory was assessed using the object recognition index (index=the time spent exploring the novel object/(the time spent exploring the novel object+the time spent exploring the familiar object)). In the test session performed 90 min after the training session, BPA-exposed male offspring not only spent more time in exploring the familiar object at the highest dose than the control, but also displayed a significantly decreased the object recognition index at the doses of 0.5, 5 and 50 mg/kg BW/day. During the test session performed 24h after the training session, BPA-treated males did not change the time spent exploring the familiar object, but had a decreased object recognition index at 5 and 50 mg/kg BW/day, when compared to control group. These findings indicate that object recognition memory was susceptible to maternal BPA exposure. Western blot analysis of hippocampi from BPA-treated male offspring revealed a decrease in Akt, phospho-Akt, p44/42 MAPK and phospho-p44/42 MAPK protein levels, compared to controls. In addition, BPA significantly inhibited the levels of phosphorylation of CREB and BDNF in the hippocampus. Our results show that maternal BPA exposure may full impair object recognition memory, and that

  11. Dopamine D1 receptor activity modulates object recognition memory consolidation in the perirhinal cortex but not in the hippocampus.

    PubMed

    Balderas, Israela; Moreno-Castilla, Perla; Bermudez-Rattoni, Federico

    2013-10-01

    It has been proposed that distributed neuronal networks in the medial temporal lobe process different characteristics of a recognition event; the hippocampus has been associated with contextual recollection while the perirhinal cortex has been linked with familiarity. Here we show that D1 dopamine receptor activity in these two structures participates differentially in object recognition memory consolidation. The D1 receptor antagonist SCH23390 was infused bilaterally 15 min before a 5 min sample phase in either rats' perirhinal cortex or dorsal hippocampus, and they were tested 90 min for short-term memory or 24 h later for long-term memory. SCH23390 impaired long-term memory when infused in the perirhinal cortex but not when infused in the hippocampus. Conversely, when the D1 receptor agonist SKF38393 was infused 10 min before a 3 min sample phase in the perirhinal cortex, long-term memory was enhanced, however, this was not observed when the D1 agonist was infused in the hippocampus. Short-term memory was spared when SCH23390 or SKF38393 were infused in the perirhinal cortex or the dorsal hippocampus suggesting that acquisition was unaffected. These results suggest that dopaminergic transmission in these medial temporal lobe structures have a differential involvement in object recognition memory consolidation. Copyright © 2013 Wiley Periodicals, Inc.

  12. Selective impairment of hippocampus and posterior hub areas in Alzheimer's disease: an MEG-based multiplex network study.

    PubMed

    Yu, Meichen; Engels, Marjolein M A; Hillebrand, Arjan; van Straaten, Elisabeth C W; Gouw, Alida A; Teunissen, Charlotte; van der Flier, Wiesje M; Scheltens, Philip; Stam, Cornelis J

    2017-03-16

    Although frequency-specific network analyses have shown that functional brain networks are altered in patients with Alzheimer's disease, the relationships between these frequency-specific network alterations remain largely unknown. Multiplex network analysis is a novel network approach to study complex systems consisting of subsystems with different types of connectivity patterns. In this study, we used magnetoencephalography to integrate five frequency-band specific brain networks in a multiplex framework. Previous structural and functional brain network studies have consistently shown that hub brain areas are selectively disrupted in Alzheimer's disease. Accordingly, we hypothesized that hub regions in the multiplex brain networks are selectively targeted in patients with Alzheimer's disease in comparison to healthy control subjects. Eyes-closed resting-state magnetoencephalography recordings from 27 patients with Alzheimer's disease (60.6 ± 5.4 years, 12 females) and 26 controls (61.8 ± 5.5 years, 14 females) were projected onto atlas-based regions of interest using beamforming. Subsequently, source-space time series for both 78 cortical and 12 subcortical regions were reconstructed in five frequency bands (delta, theta, alpha 1, alpha 2 and beta band). Multiplex brain networks were constructed by integrating frequency-specific magnetoencephalography networks. Functional connections between all pairs of regions of interests were quantified using a phase-based coupling metric, the phase lag index. Several multiplex hub and heterogeneity metrics were computed to capture both overall importance of each brain area and heterogeneity of the connectivity patterns across frequency-specific layers. Different nodal centrality metrics showed consistently that several hub regions, particularly left hippocampus, posterior parts of the default mode network and occipital regions, were vulnerable in patients with Alzheimer's disease compared to control subjects. Of note

  13. ANI inactivation: unconditioned anxiolytic effects of anisomycin in the ventral hippocampus.

    PubMed

    Greenberg, Anastasia; Ward-Flanagan, Rachel; Dickson, Clayton T; Treit, Dallas

    2014-11-01

    Although hippocampal function is typically described in terms of memory, recent evidence suggests a differentiation along its dorsal/ventral axis, with dorsal regions serving memory and ventral regions serving emotion. While long-term memory is thought to be dependent on de novo protein synthesis because it is blocked by translational inhibitors such as anisomycin (ANI), online (moment-to-moment) functions of the hippocampus (such as unconditioned emotional responding) should not be sensitive to such manipulations since they are unlikely to involve neuroplasticity. However, ANI has recently been shown to suppress neural activity which suggests (1) that protein synthesis is critical for neural function and (2) that paradigms using ANI are confounded by its inactivating effects. We tested this idea using a neurobehavioral assay which compared the influence of intrahippocampal infusions of ANI at dorsal and ventral sites on unconditioned emotional behavior of rats. We show that ANI infusions in ventral, but not dorsal, hippocampus produced a suppression of anxiety-related responses in two well-established rodent tests: the elevated plus maze and shock-probe burying tests. These results are similar to those previously observed when ventral hippocampal activity is directly suppressed (e.g., by using sodium channel blockers). The present study offers compelling behavioral evidence for the proposal that ANI adversely affects ongoing neural function and therefore its influence is not simply limited to impairing the consolidation of long-term memories Copyright © 2014 Wiley Periodicals, Inc.

  14. Extensive training and hippocampus or striatum lesions: effect on place and response strategies.

    PubMed

    Jacobson, Tara K; Gruenbaum, Benjamin F; Markus, Etan J

    2012-02-01

    The hippocampus has been linked to spatial navigation and the striatum to response learning. The current study focuses on how these brain regions continue to interact when an animal is very familiar with the task and the environment and must continuously switch between navigation strategies. Rats were trained to solve a plus maze using a place or a response strategy on different trials within a testing session. A room cue (illumination) was used to indicate which strategy should be used on a given trial. After extensive training, animals underwent dorsal hippocampus, dorsal lateral striatum or sham lesions. As expected hippocampal lesions predominantly caused impairment on place but not response trials. Striatal lesions increased errors on both place and response trials. Competition between systems was assessed by determining error type. Pre-lesion and sham animals primarily made errors to arms associated with the wrong (alternative) strategy, this was not found after lesions. The data suggest a qualitative change in the relationship between hippocampal and striatal systems as a task is well learned. During acquisition the two systems work in parallel, competing with each other. After task acquisition, the two systems become more integrated and interdependent. The fact that with extensive training (as something becomes a "habit"), behaviors become dependent upon the dorsal lateral striatum has been previously shown. The current findings indicate that dorsal lateral striatum involvement occurs even when the behavior is spatial and continues to require hippocampal processing.

  15. Impaired adenosine monophosphate-activated protein kinase signalling in dorsal root ganglia neurons is linked to mitochondrial dysfunction and peripheral neuropathy in diabetes

    PubMed Central

    Smith, Darrell R.; Saleh, Ali; Schapansky, Jason; Marquez, Alexandra; Gomes, Suzanne; Akude, Eli; Morrow, Dwane; Calcutt, Nigel A.; Fernyhough, Paul

    2012-01-01

    Mitochondrial dysfunction occurs in sensory neurons and may contribute to distal axonopathy in animal models of diabetic neuropathy. The adenosine monophosphate-activated protein kinase and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) signalling axis senses the metabolic demands of cells and regulates mitochondrial function. Studies in muscle, liver and cardiac tissues have shown that the activity of adenosine monophosphate-activated protein kinase and PGC-1α is decreased under hyperglycaemia. In this study, we tested the hypothesis that deficits in adenosine monophosphate-activated protein kinase/PGC-1α signalling in sensory neurons underlie impaired axonal plasticity, suboptimal mitochondrial function and development of neuropathy in rodent models of type 1 and type 2 diabetes. Phosphorylation and expression of adenosine monophosphate-activated protein kinase/PGC-1α and mitochondrial respiratory chain complex proteins were downregulated in dorsal root ganglia of both streptozotocin-diabetic rats and db/db mice. Adenoviral-mediated manipulation of endogenous adenosine monophosphate-activated protein kinase activity using mutant proteins modulated neurotrophin-directed neurite outgrowth in cultures of sensory neurons derived from adult rats. Addition of resveratrol to cultures of sensory neurons derived from rats after 3–5 months of streptozotocin-induced diabetes, significantly elevated adenosine monophosphate-activated protein kinase levels, enhanced neurite outgrowth and normalized mitochondrial inner membrane polarization in axons. The bioenergetics profile (maximal oxygen consumption rate, coupling efficiency, respiratory control ratio and spare respiratory capacity) was aberrant in cultured sensory neurons from streptozotocin-diabetic rats and was corrected by resveratrol treatment. Finally, resveratrol treatment for the last 2 months of a 5-month period of diabetes reversed thermal hypoalgesia and attenuated foot skin

  16. Taurine Pretreatment Prevents Isoflurane-Induced Cognitive Impairment by Inhibiting ER Stress-Mediated Activation of Apoptosis Pathways in the Hippocampus in Aged Rats.

    PubMed

    Zhang, Yanan; Li, Dongliang; Li, Haiou; Hou, Dailiang; Hou, Jingdong

    2016-10-01

    Isoflurane, a commonly used inhalation anesthetic, may induce neurocognitive deficits, especially in elderly patients after surgery. Recent study demonstrated that isoflurane caused endoplasmic reticulum (ER) stress and subsequent neuronal apoptosis in the brain, contributing to cognitive deficits. Taurine, a major intracellular free amino acid, has been shown to inhibit ER stress and neuronal apoptosis in several neurological disorders. Here, we examined whether taurine can prevent isoflurane-induced ER stress and cognitive impairment in aged rats. Thirty minutes prior to a 4-h 1.3 % isoflurane exposure, aged rats were treated with vehicle or taurine at low, middle and high doses. Aged rats without any treatment served as control. The brains were harvested 6 h after isoflurane exposure for molecular measurements, and behavioral study was performed 2 weeks later. Compared with control, isoflurane increased expression of hippocampal ER stress biomarkers including glucose-regulated protein 78, phosphorylated (P-) inositol-requiring enzyme 1, P-eukaryotic initiation factor 2-α (EIF2α), activating transcription factor 4 (ATF-4), cleaved ATF-6 and C/EBP homologous protein, along with activation of apoptosis pathways as indicated by decreased B cell lymphoma 2 (BCL-2)/BCL2-associated X protein, increased expressions of cytochrome-c and cleaved caspase-3. Taurine pretreatment dose-dependently inhibited isoflurane-induced increase in expression of ER stress biomarkers except for P-EIF2α and ATF-4, and reversed isoflurane-induced changes in apoptosis-related proteins. Moreover, isoflurane caused spatial working memory deficits in aged rats, which were prevented by taurine pretreatment. The results indicate that taurine pretreatment prevents anesthetic isoflurane-induced cognitive impairment by inhibiting ER stress-mediated activation of apoptosis pathways in the hippocampus in aged rats.

  17. Aging-induced proteostatic changes in the rat hippocampus identify ARP3, NEB2 and BRAG2 as a molecular circuitry for cognitive impairment.

    PubMed

    Ottis, Philipp; Topic, Bianca; Loos, Maarten; Li, Ka Wan; de Souza, Angelica; Schulz, Daniela; Smit, August B; Huston, Joseph P; Korth, Carsten

    2013-01-01

    Disturbed proteostasis as a particular phenotype of the aging organism has been advanced in C. elegans experiments and is also conceived to underlie neurodegenerative diseases in humans. Here, we investigated whether particular changes in non-disease related proteostasis can be identified in the aged mammalian brain, and whether a particular signature of aberrant proteostasis is related to behavioral performance of learning and memory. Young (adult, n = 30) and aged (2 years, n = 50) Wistar rats were tested in the Morris Water Maze (MWM) to distinguish superior and inferior performers. For both young and old rats, the best and worst performers in the MWM were selected and the insoluble proteome, termed aggregome, was purified from the hippocampus as evidence for aberrant proteostasis. Quantitative proteomics (iTRAQ) was performed. The aged inferior performers were considered as a model for spontaneous, age-associated cognitive impairment. Whereas variability of the insoluble proteome increased with age, absolute changes in the levels of insoluble proteins were small compared to the findings in the whole C. elegans insoluble proteome. However, we identified proteins with aberrant proteostasis in aging. For the cognitively impaired rats, we identified a changed molecular circuitry of proteins selectively involved in F-actin remodeling, synapse building and long-term depression: actin related protein 3 (ARP3), neurabin II (NEB2) and IQ motif and SEC7 domain-containing protein 1 (BRAG2). We demonstrate that aberrant proteostasis is a specific phenotype of brain aging in mammals. We identify a distinct molecular circuitry where changes in proteostasis are characteristic for poor learning and memory performance in the wild type, aged rat. Our findings 1. establish the search for aberrant proteostasis as a successful strategy to identify neuronal dysfunction in deficient cognitive behavior, 2. reveal a previously unknown functional network of proteins (ARP3, NEB2, BRAG2

  18. Aging-Induced Proteostatic Changes in the Rat Hippocampus Identify ARP3, NEB2 and BRAG2 as a Molecular Circuitry for Cognitive Impairment

    PubMed Central

    Ottis, Philipp; Topic, Bianca; Loos, Maarten; Li, Ka Wan; de Souza, Angelica; Schulz, Daniela; Smit, August B.; Huston, Joseph P.; Korth, Carsten

    2013-01-01

    Disturbed proteostasis as a particular phenotype of the aging organism has been advanced in C. elegans experiments and is also conceived to underlie neurodegenerative diseases in humans. Here, we investigated whether particular changes in non-disease related proteostasis can be identified in the aged mammalian brain, and whether a particular signature of aberrant proteostasis is related to behavioral performance of learning and memory. Young (adult, n = 30) and aged (2 years, n = 50) Wistar rats were tested in the Morris Water Maze (MWM) to distinguish superior and inferior performers. For both young and old rats, the best and worst performers in the MWM were selected and the insoluble proteome, termed aggregome, was purified from the hippocampus as evidence for aberrant proteostasis. Quantitative proteomics (iTRAQ) was performed. The aged inferior performers were considered as a model for spontaneous, age-associated cognitive impairment. Whereas variability of the insoluble proteome increased with age, absolute changes in the levels of insoluble proteins were small compared to the findings in the whole C. elegans insoluble proteome. However, we identified proteins with aberrant proteostasis in aging. For the cognitively impaired rats, we identified a changed molecular circuitry of proteins selectively involved in F-actin remodeling, synapse building and long-term depression: actin related protein 3 (ARP3), neurabin II (NEB2) and IQ motif and SEC7 domain-containing protein 1 (BRAG2). We demonstrate that aberrant proteostasis is a specific phenotype of brain aging in mammals. We identify a distinct molecular circuitry where changes in proteostasis are characteristic for poor learning and memory performance in the wild type, aged rat. Our findings 1. establish the search for aberrant proteostasis as a successful strategy to identify neuronal dysfunction in deficient cognitive behavior, 2. reveal a previously unknown functional network of proteins (ARP3, NEB2, BRAG2

  19. Major Impairments of Glutamatergic Transmission and Long-Term Synaptic Plasticity in the Hippocampus of Mice Lacking the Melanin-Concentrating Hormone Receptor-1

    PubMed Central

    Pachoud, Bastien; Adamantidis, Antoine; Ravassard, Pascal; Luppi, Pierre-Hervé; Grisar, Thierry; Lakaye, Bernard

    2010-01-01

    The hypothalamic neuropeptide melanin-concentrating hormone (MCH) plays important roles in energy homeostasis, anxiety, and sleep regulation. Since the MCH receptor-1 (MCH-R1), the only functional receptor that mediates MCH functions in rodents, facilitates behavioral performance in hippocampus-dependent learning tasks, we investigated whether glutamatergic transmission in CA1 pyramidal cells could be modulated in mice lacking the MCH-R1 gene (MCH-R1−/−). We found that both α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartate (NMDA) receptor-mediated transmissions were diminished in the mutant mice compared with their controls. This deficit was explained, at least in part, by a postsynaptic down-regulation of these receptors since the amplitude of miniature excitatory postsynaptic currents and the NMDA/AMPA ratio were decreased. Long-term synaptic potentiation (LTP) was also impaired in MCH-R1−/− mice. This was due to an altered induction, rather than an impaired, expression because repeating the induction stimulus restored LTP to a normal magnitude. In addition, long-term synaptic depression was strongly diminished in MCH-R1−/− mice. These results suggest that MCH exerts a facilitatory effect on CA1 glutamatergic synaptic transmission and long-term synaptic plasticity. Recently, it has been shown that MCH neurons fire exclusively during sleep and mainly during rapid eye movement sleep. Thus these findings provide a mechanism by which sleep might facilitate memory consolidation. PMID:20592115

  20. Age-related spatial cognitive impairment is correlated with a decrease in ChAT in the cerebral cortex, hippocampus and forebrain of SAMP8 mice.

    PubMed

    Wang, Feng; Chen, Hong; Sun, Xiaojiang

    2009-05-01

    At present, the mechanisms underlying cognitive disorders remain unclear. The senescence-accelerated mice (SAM) prone/8 (P8) has been proposed as a useful model for the study of aging, and SAM resistant/1 (R1) is its control as a normal aging strain. The purpose of this study was to investigate choline acetyltransferase (ChAT) expression in SAM brain. The age-related decline of learning and memory ability in P8 mice (4, 8 and 12 months old, n=10 for each group) was proved in Morris water maze test (MWM). After the behavioral test, protein and mRNA levels of ChAT were determined in the cerebral cortex, hippocampus and forebrain by means of immunostaining, Western blotting, and real time quantitative PCR (QPCR). Comparing with 4-month-old P8 and R1, 8- and 12-month-old P8 showed age-related cognitive impairment in MWM test. The latencies of the 4-month-old P8 in a hidden platform trial were significantly shorter, and the retention time was significantly longer than that of the older P8 groups. In addition, significantly low level of ChAT protein was observed in older P8 groups. Comparing with the 4-month-old P8, ChAT mRNA in the 12-month-old P8 declined significantly in all three regions of P8 brain. Pearson correlation test showed that the latencies in the MWM were positively correlated with the level of ChAT in P8. Such phenomenon could not be detected in normal aging R1 mice. These findings suggest that the decrease of ChAT in P8 mice was responsible for the age-related learning and memory impairments in some sense.

  1. Developmental iodine deficiency and hypothyroidism impair neural development, up-regulate caveolin-1 and down-regulate synaptophysin in rat hippocampus.

    PubMed

    Gong, J; Dong, J; Wang, Y; Xu, H; Wei, W; Zhong, J; Liu, W; Xi, Q; Chen, J

    2010-02-01

    Developmental iodine deficiency leads to inadequate thyroid hormone, which damages the hippocampus. In the present study, we implicate hippocampal caveolin-1 and synaptophysin in developmental iodine deficiency and hypothyroidism. Two developmental rat models were established: pregnant rats were administered either an iodine-deficient diet or propylthiouracil (PTU)-adulterated (5 p.p.m. or 15 p.p.m.) drinking water from gestational day 6 until postnatal day (PN) 28. Nissl staining and the levels of caveolin-1 and synaptophysin in several hippocampal subregions were assessed on PN14, PN21, PN28 and PN42. The results obtained show that surviving cells in the iodine-deficient and PTU-treated rats were lower than in controls. Up-regulation of caveolin-1 and down-regulation of synaptophysin were observed in the iodine-deficient and PTU-treated rats. Our findings implicate decreases in the number of surviving cells and alterations in the levels of caveolin-1 and synaptophysin in the impairments in neural development induced by developmental iodine deficiency and hypothyroidism.

  2. Impacts of CD33 Genetic Variations on the Atrophy Rates of Hippocampus and Parahippocampal Gyrus in Normal Aging and Mild Cognitive Impairment.

    PubMed

    Wang, Wen-Ying; Liu, Ying; Wang, Hui-Fu; Tan, Lin; Sun, Fu-Rong; Tan, Meng-Shan; Tan, Chen-Chen; Jiang, Teng; Tan, Lan; Yu, Jin-Tai

    2017-03-01

    The cluster of differentiation 33 (CD33) has been proved as a susceptibility locus associated with late-onset Alzheimer's disease (LOAD) based on recent genetic studies. Numerous studies have shown that multiple neuroimaging measures are potent predictors of AD risk and progression, and these measures are also affected by genetic variations in AD. Figuring out the association between CD33 genetic variations and AD-related brain atrophy may shed light on the underlying mechanisms of CD33-related AD pathogenesis. Thus, we investigated the influence of CD33 genotypes on AD-related brain atrophy to clarify the possible means by which CD33 impacts AD. A total of 48 individuals with probable AD, 483 mild cognitive impairment, and 281 cognitively normal controls were recruited from the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. We investigated the influence of CD33 SNPs on hippocampal volume, parahippocampal gyrus volume, posterior cingulate volume, middle temporal volume, hippocampus CA1 subregion volume, and entorhinal cortex thickness. We found that brain regions significantly affected by CD33 genetic variations were restricted to hippocampal and parahippocampal gyrus in hybrid population, which were further validated in subpopulation (MCI and NC) analysis. These findings reaffirm the importance of the hippocampal and parahippocampal gyrus in AD pathogenesis, and present evidences for the CD33 variations influence on the atrophy of specific AD-related brain structures. Our findings raise the possibility that CD33 polymorphisms contribute to the AD risk by altering the neuronal degeneration of hippocampal and parahippocampal gyrus.

  3. TNF-α Differentially Regulates Synaptic Plasticity in the Hippocampus and Spinal Cord by Microglia-Dependent Mechanisms after Peripheral Nerve Injury.

    PubMed

    Liu, Yong; Zhou, Li-Jun; Wang, Jun; Li, Dai; Ren, Wen-Jie; Peng, Jiyun; Wei, Xiao; Xu, Ting; Xin, Wen-Jun; Pang, Rui-Ping; Li, Yong-Yong; Qin, Zhi-Hai; Murugan, Madhuvika; Mattson, Mark P; Wu, Long-Jun; Liu, Xian-Guo

    2017-01-25

    Clinical studies show that chronic pain is accompanied by memory deficits and reduction in hippocampal volume. Experimental studies show that spared nerve injury (SNI) of the sciatic nerve induces long-term potentiation (LTP) at C-fiber synapses in spinal dorsal horn, but impairs LTP in the hippocampus. The opposite changes may contribute to neuropathic pain and memory deficits, respectively. However, the cellular and molecular mechanisms underlying the functional synaptic changes are unclear. Here, we show that the dendrite lengths and spine densities are reduced significantly in hippocampal CA1 pyramidal neurons, but increased in spinal neurokinin-1-positive neurons in mice after SNI, indicating that the excitatory synaptic connectivity is reduced in hippocampus but enhanced in spinal dorsal horn in this neuropathic pain model. Mechanistically, tumor necrosis factor-alpha (TNF-α) is upregulated in bilateral hippocampus and in ipsilateral spinal dorsal horn, whereas brain-derived neurotrophic factor (BDNF) is decreased in the hippocampus but increased in the ipsilateral spinal dorsal horn after SNI. Importantly, the SNI-induced opposite changes in synaptic connectivity and BDNF expression are prevented by genetic deletion of TNF receptor 1 in vivo and are mimicked by TNF-α in cultured slices. Furthermore, SNI activated microglia in both spinal dorsal horn and hippocampus; pharmacological inhibition or genetic ablation of microglia prevented the region-dependent synaptic changes, neuropathic pain, and memory deficits induced by SNI. The data suggest that neuropathic pain involves different structural synaptic alterations in spinal and hippocampal neurons that are mediated by overproduction of TNF-α and microglial activation and may underlie chronic pain and memory deficits.

  4. Enhancement of nose-to-brain delivery of basic fibroblast growth factor for improving rat memory impairments induced by co-injection of β-amyloid and ibotenic acid into the bilateral hippocampus.

    PubMed

    Feng, Chengcheng; Zhang, Chi; Shao, Xiayan; Liu, Qingfeng; Qian, Yong; Feng, Liang; Chen, Jie; Zha, Yuan; Zhang, Qizhi; Jiang, Xinguo

    2012-02-28

    Basic fibroblast growth factor (bFGF) delivery to the brain of animals appears to be an emerging potential therapeutic approach to neurodegenerative diseases, such as Alzheimer's disease (AD). The intranasal route of administration could provide an alternative to intracerebroventricular infusion. A nasal spray of bFGF had been developed previously and the objective of the present study was to investigate whether bFGF nasal spray could enhance brain uptake of bFGF and ameliorate memory impairment induced by co-injection of β-amyloid(25-35) and ibotenic acid into bilateral hippocampus of rats. The results of brain uptake study showed that the AUC(0-12h) of bFGF nasal spray in olfactory bulb, cerebrum, cerebellum and hippocampus was respectively 2.47, 2.38, 2.56 and 2.19 times that of intravenous bFGF solution, and 1.11, 1.95, 1.40 and 1.93 times that of intranasal bFGF solution, indicating that intranasal administration of bFGF nasal spray was an effective means of delivering bFGF to the brain, especially to cerebrum and hippocampus. In Morris water maze tasks, intravenous administration of bFGF solution at high dose (40 μg/kg) showed little improvement on spatial memory impairment. In contrast, bFGF solution of the same dose following intranasal administration could significantly ameliorate spatial memory impairment. bFGF nasal spray obviously improved spatial memory impairment even at a dose half (20 μg/kg) of bFGF solution, recovered their acetylcholinesterase and choline acetyltransferase activity to the sham control level, and alleviated neuronal degeneration in rat hippocampus, indicating neuroprotective effects on the central nerve system. In a word, bFGF nasal spray may be a new formulation of great potential for treating AD.

  5. The influence of cannabinoids on learning and memory processes of the dorsal striatum.

    PubMed

    Goodman, Jarid; Packard, Mark G

    2015-11-01

    Extensive evidence indicates that the mammalian endocannabinoid system plays an integral role in learning and memory. Our understanding of how cannabinoids influence memory comes predominantly from studies examining cognitive and emotional memory systems mediated by the hippocampus and amygdala, respectively. However, recent evidence suggests that cannabinoids also affect habit or stimulus-response (S-R) memory mediated by the dorsal striatum. Studies implementing a variety of maze tasks in rats indicate that systemic or intra-dorsolateral striatum infusions of cannabinoid receptor agonists or antagonists impair habit memory. In mice, cannabinoid 1 (CB1) receptor knockdown can enhance or impair habit formation, whereas Δ(9)THC tolerance enhances habit formation. Studies in human cannabis users also suggest an enhancement of S-R/habit memory. A tentative conclusion based on the available data is that acute disruption of the endocannabinoid system with either agonists or antagonists impairs, whereas chronic cannabinoid exposure enhances, dorsal striatum-dependent S-R/habit memory. CB1 receptors are required for multiple forms of striatal synaptic plasticity implicated in memory, including short-term and long-term depression. Interactions with the hippocampus-dependent memory system may also have a role in some of the observed effects of cannabinoids on habit memory. The impairing effect often observed with acute cannabinoid administration argues for cannabinoid-based treatments for human psychopathologies associated with a dysfunctional habit memory system (e.g. post-traumatic stress disorder and drug addiction/relapse). In addition, the enhancing effect of repeated cannabinoid exposure on habit memory suggests a novel neurobehavioral mechanism for marijuana addiction involving the dorsal striatum-dependent memory system. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. {gamma}-aminobutyric acid{sub A} (GABA{sub A}) receptor regulates ERK1/2 phosphorylation in rat hippocampus in high doses of Methyl Tert-Butyl Ether (MTBE)-induced impairment of spatial memory

    SciTech Connect

    Zheng Gang; Zhang Wenbin; Zhang Yun; Chen Yaoming; Liu Mingchao; Yao Ting; Yang Yanxia; Zhao Fang; Li Jingxia; Huang Chuanshu; Luo Wenjing Chen Jingyuan

    2009-04-15

    Experimental and occupational exposure to Methyl Tert-Butyl Ether (MTBE) has been reported to induce neurotoxicological and neurobehavioral effects, such as headache, nausea, dizziness, and disorientation, etc. However, the molecular mechanisms involved in MTBE-induced neurotoxicity are still not well understood. In the present study, we investigated the effects of MTBE on spatial memory and the expression and function of GABA{sub A} receptor in the hippocampus. Our results demonstrated that intraventricular injection of MTBE impaired the performance of the rats in a Morris water maze task, and significantly increased the expression of GABA{sub A} receptor {alpha}1 subunit in the hippocampus. The phosphorylation of ERK1/2 decreased after the MTBE injection. Furthermore, the decreased ability of learning and the reduction of phosphorylated ERK1/2 level of the MTBE-treated rats was partly reversed by bicuculline injected 30 min before the training. These results suggested that MTBE exposure could result in impaired spatial memory. GABA{sub A} receptor may play an important role in the MTBE-induced impairment of learning and memory by regulating the phosphorylation of ERK in the hippocampus.

  7. Impaired hippocampus-dependent spatial flexibility and sociability represent autism-like phenotypes in GluK2 mice.

    PubMed

    Micheau, Jacques; Vimeney, Alice; Normand, Elisabeth; Mulle, Christophe; Riedel, Gernot

    2014-09-01

    Autism is a complex neurodevelopmental disorder with high heritability. grik2 (which encodes the GluK2 subunit of kainate receptors) has been identified as a susceptibility gene in Autism Spectrum Disorders (ASD), but its role in the core and associated symptoms of ASD still remains elusive. We used mice lacking GluK2 (GluK2 KO) to examine their endophenotype with a view to modeling aspects of autism, including social deficits, stereotyped and repetitive behavior and decreased cognitive abilities. Anxiety was recorded in the elevated plus maze, social behavior in a three-chamber apparatus, and cognition in different water maze protocols. Deletion of the GluK2 gene reduced locomotor activity and sociability as indicated by the social interaction task. In addition, GluK2 KO mice learnt to locate a hidden platform in a water maze surrounded by a curtain with hanging cues faster than wild-type mice. They maintained a bias toward the target quadrant when some of these cues were removed, at which point wild-types orthogonalized the behavior and showed no memory. However, GluK2 KO mice were impaired in spatial reversal learning. These behavioral data together with previously published electrophysiology showing severe anomalies in CA3 network activity, suggest a computational shift in this network for enhanced propensity of pattern completion that would explain the loss of behavioral flexibility in GluK2 KO mice. Although a single mutation cannot recapitulate the entire core symptoms of ASD, our data provide evidence for glutamatergic dysfunction underlying a number of social- and cognition-related phenotypes relevant to ASD.

  8. Discrimination between Alzheimer disease, mild cognitive impairment, and normal aging by using automated segmentation of the hippocampus.

    PubMed

    Colliot, Olivier; Chételat, Gaël; Chupin, Marie; Desgranges, Béatrice; Magnin, Benoît; Benali, Habib; Dubois, Bruno; Garnero, Line; Eustache, Francis; Lehéricy, Stéphane

    2008-07-01

    To prospectively evaluate the accuracy of automated hippocampal volumetry to help distinguish between patients with Alzheimer disease (AD), patients with mild cognitive impairment (MCI), and elderly controls, by using established criteria for patients with AD and MCI as the reference standard. The regional ethics committee approved the study and written informed consent was obtained from all participants. The study included 25 patients with AD (11 men, 14 women; mean age +/- standard deviation [SD], 73 years +/- 6; Mini-Mental State Examination (MMSE) score, 24.4 +/- 2.7), 24 patients with amnestic MCI (10 men, 14 women; mean age +/- SD, 74 years +/- 8; MMSE score, 27.2 +/- 1.4) and 25 elderly healthy controls (13 men, 12 women; mean age +/- SD, 64 years +/- 8). For each participant, the hippocampi were automatically segmented on three-dimensional T1-weighted magnetic resonance (MR) images with high spatial resolution. Segmentation was performed by using recently developed software that allows fast segmentation with minimal user input. Group differences in hippocampal volume were assessed by using Student t tests. To obtain robust estimates of P values, the correct classification rate, sensitivity, and specificity, bootstrap methods were used. Significant hippocampal volume reductions were detected in all groups of patients (-32% in AD patients vs controls, P < .001; -19% in MCI patients vs controls, P < .001; and -15% in AD patients vs MCI patients, P < .01). Individual classification on the basis of hippocampal volume resulted in 84% correct classification (sensitivity, 84%; specificity, 84%) between AD patients and controls and 73% correct classification (sensitivity, 75%; specificity, 70%) between MCI patients and controls. This automated method can serve as an alternative to manual tracing and may thus prove useful in assisting with the diagnosis of AD. (c) RSNA, 2008.

  9. The ventral hippocampus is necessary for expressing a spatial memory.

    PubMed

    Loureiro, Michael; Lecourtier, Lucas; Engeln, Michel; Lopez, Joëlle; Cosquer, Brigitte; Geiger, Karin; Kelche, Christian; Cassel, Jean-Christophe; Pereira de Vasconcelos, Anne

    2012-01-01

    Current views posit the dorsal hippocampus (DHipp) as contributing to spatial memory processes. Conversely, the ventral hippocampus (VHipp) modulates stress, emotions and affects. Arguments supporting this segregation include differences in (i) connectivity: the DHipp is connected with the entorhinal cortex which receives visuospatial neocortical inputs; the VHipp is connected with both the amygdala and hypothalamus, (ii) electrophysiological characteristics: there is a larger proportion of place cells in the DHipp than in the VHipp, and an increasing dorsoventral gradient in the size of place fields, suggesting less refined spatial coding in the VHipp, and (iii) consequences of lesions: spatial memory is altered after DHipp lesions, less dramatically, sometimes not, after VHipp lesions. Using reversible inactivation, we report in rats, that lidocaine infusions into the DHipp or VHipp right before a probe trial impair retrieval performance in a water-maze task. This impairment was found at two post-acquisition delays compatible with recent memory (1 and 5 days). Pre-training blockade of the VHipp did not prevent task acquisition and drug-free retrieval, on the contrary to pre-training blockade of DHipp, which altered performance in a subsequent drug-free probe trial. Complementary experiments excluded possible locomotor, sensorimotor, motivational or anxiety-related biases from data interpretation. Our conclusion is that a spatial memory can be acquired with the DHipp, less efficiently with the VHipp, and that the retrieval of such a memory and/or the expression of its representation engages the dorsoventral axis of the hippocampus when the task has been learnt with an entirely functional hippocampus.

  10. Levels of neural progenitors in the hippocampus predict memory impairment and relapse to drug seeking as a function of excessive methamphetamine self-administration.

    PubMed

    Recinto, Patrick; Samant, Anjali Rose H; Chavez, Gustavo; Kim, Airee; Yuan, Clara J; Soleiman, Matthew; Grant, Yanabel; Edwards, Scott; Wee, Sunmee; Koob, George F; George, Olivier; Mandyam, Chitra D

    2012-04-01

    Methamphetamine affects the hippocampus, a brain region crucial for learning and memory, as well as relapse to drug seeking. Rats self-administered methamphetamine for 1 h twice weekly (intermittent-short-I-ShA), 1 h daily (limited-short-ShA), or 6 h daily (extended-long-LgA) for 22 sessions. After 22 sessions, rats from each access group were withdrawn from self-administration and underwent spatial memory (Y-maze) and working memory (T-maze) tests followed by extinction and reinstatement to methamphetamine seeking or received one intraperitoneal injection of 5-bromo-2'-deoxyuridine (BrdU) to label progenitors in the hippocampal subgranular zone (SGZ) during the synthesis phase. Two-hour-old and 28-day-old surviving BrdU-immunoreactive cells were quantified. I-ShA rats performed better on the Y-maze and had a greater number of 2-h-old SGZ BrdU cells than nondrug controls. LgA rats, but not ShA rats, performed worse on the Y- and T-maze and had a fewer number of 2-h-old SGZ BrdU cells than nondrug and I-ShA rats, suggesting that new hippocampal progenitors, decreased by methamphetamine, were correlated with impairment in the acquisition of new spatial cues. Analyses of addiction-related behaviors after withdrawal and extinction training revealed methamphetamine-primed reinstatement of methamphetamine-seeking behavior in all three groups (I-ShA, ShA, and LgA), and this effect was enhanced in LgA rats compared with I-ShA and ShA rats. Protracted withdrawal from self-administration enhanced the survival of SGZ BrdU cells, and methamphetamine seeking during protracted withdrawal enhanced Fos expression in the dentate gyrus and medial prefrontal cortex in LgA rats to a greater extent than in ShA and I-ShA rats. These results indicate that changes in the levels of the proliferation and survival of hippocampal neural progenitors and neuronal activation of hippocampal granule cells predict the effects of methamphetamine self-administration (limited vs extended access) on

  11. Levels of Neural Progenitors in the Hippocampus Predict Memory Impairment and Relapse to Drug Seeking as a Function of Excessive Methamphetamine Self-Administration

    PubMed Central

    Recinto, Patrick; Samant, Anjali Rose H; Chavez, Gustavo; Kim, Airee; Yuan, Clara J; Soleiman, Matthew; Grant, Yanabel; Edwards, Scott; Wee, Sunmee; Koob, George F; George, Olivier; Mandyam, Chitra D

    2012-01-01

    Methamphetamine affects the hippocampus, a brain region crucial for learning and memory, as well as relapse to drug seeking. Rats self-administered methamphetamine for 1 h twice weekly (intermittent-short-I-ShA), 1 h daily (limited-short-ShA), or 6 h daily (extended-long-LgA) for 22 sessions. After 22 sessions, rats from each access group were withdrawn from self-administration and underwent spatial memory (Y-maze) and working memory (T-maze) tests followed by extinction and reinstatement to methamphetamine seeking or received one intraperitoneal injection of 5-bromo-2′-deoxyuridine (BrdU) to label progenitors in the hippocampal subgranular zone (SGZ) during the synthesis phase. Two-hour-old and 28-day-old surviving BrdU-immunoreactive cells were quantified. I-ShA rats performed better on the Y-maze and had a greater number of 2-h-old SGZ BrdU cells than nondrug controls. LgA rats, but not ShA rats, performed worse on the Y- and T-maze and had a fewer number of 2-h-old SGZ BrdU cells than nondrug and I-ShA rats, suggesting that new hippocampal progenitors, decreased by methamphetamine, were correlated with impairment in the acquisition of new spatial cues. Analyses of addiction-related behaviors after withdrawal and extinction training revealed methamphetamine-primed reinstatement of methamphetamine-seeking behavior in all three groups (I-ShA, ShA, and LgA), and this effect was enhanced in LgA rats compared with I-ShA and ShA rats. Protracted withdrawal from self-administration enhanced the survival of SGZ BrdU cells, and methamphetamine seeking during protracted withdrawal enhanced Fos expression in the dentate gyrus and medial prefrontal cortex in LgA rats to a greater extent than in ShA and I-ShA rats. These results indicate that changes in the levels of the proliferation and survival of hippocampal neural progenitors and neuronal activation of hippocampal granule cells predict the effects of methamphetamine self-administration (limited vs extended

  12. Influence of dorsal hippocampal lesions and MMP inhibitors on spontaneous recovery following a habituation/classical conditioning head-shake task.

    PubMed

    Wiediger, Roberta V; Wright, John W

    2009-11-01

    The present investigation combined a classical conditioning paradigm with a head-shake response (HSR) habituation task in order to evaluate the importance of dorsal hippocampal neural plasticity to spontaneous recovery. In the first experiment animals exhibited rapid HSR habituation (air stimulus to the ear) and an 85% level of spontaneous recovery following a 24 h inter-session interval. The addition of a brief tone prior to the air stimulus produced a similar pattern of habituation during the first session, but the level of spontaneous recovery was reduced (44%) during Session II. In a second experiment dorsal hippocampal lesioned rats placed on this tone/HSR paradigm responded with an 87% level of spontaneous recovery during Session II; while neocortex lesioned control rats indicated significantly reduced levels of spontaneous recovery (55%). In a third experiment bilateral injections of a general MMP inhibitor, FN-439, into the dorsal hippocampus resulted in high levels of spontaneous recovery (81%); while control rats injected with artificial cerebrospinal fluid displayed a significant attenuation of spontaneous recovery (45%). Finally, animals bilaterally injected with a specific MMP-3 inhibitor into the dorsal hippocampus indicated very similar results to those obtained following FN-439 injection. These findings indicate that animals prepared with dorsal hippocampal lesions, or injections with an MMP inhibitor, revealed an impaired association between the tone and air stimulus thus maximum spontaneous recovery was present 24 h later. Thus, it appears that the dorsal hippocampus influences habituation by conserving responses and reducing spontaneous recovery when a temporally contingent signaling cue is present.

  13. The role of the hippocampus in instrumental conditioning.

    PubMed

    Corbit, L H; Balleine, B W

    2000-06-01

    Considerable evidence suggests that, in instrumental conditioning, rats can encode both the specific action-outcome associations to which they are exposed and the degree to which an action is causal in producing its associated outcome. Three experiments assessed the involvement of the hippocampus in encoding these aspects of instrumental learning. In each study, rats with electrolytic lesions of the dorsal hippocampus and sham-lesioned controls were trained while hungry to press two levers, each of which delivered a unique food outcome. Experiments 1A and 1B used an outcome devaluation procedure to assess the effects of the lesion on encoding the action-outcome relationship. After training, one of the two outcomes was devalued using a specific satiety procedure, after which performance on the two levers was assessed in a choice extinction test. The lesion had no detectable effect on either the acquisition of instrumental performance or on the rats' sensitivity to outcome devaluation; lesion and sham groups both reduced responding on the lever associated with the devalued outcome compared with the other lever. In experiment 2, the sensitivity of hippocampal rats to the causal efficacy of their actions was assessed by selectively degrading the contingency between one of the actions and its associated outcome. Whereas sham rats selectively reduced performance on the lever for which the action-outcome contingency had been degraded, hippocampal rats did not. These results suggest that, in instrumental conditioning, lesions of the dorsal hippocampus selectively impair the ability of rats to represent the causal relationship between an action and its consequences.

  14. The molecular cascades of long-term potentiation underlie memory consolidation of one-trial avoidance in the CA1 region of the dorsal hippocampus, but not in the basolateral amygdala or the neocortex.

    PubMed

    Izquierdo, Iván; Bevilaqua, Lia R M; Rossato, Janine I; da Silva, Weber C; Bonini, Juliana; Medina, Jorge H; Cammarota, Martín

    2008-10-01

    Data accumulated through the past 15 years showed that memory consolidation of one-trial avoidance learning relies on a sequence of molecular events in the CA1 region of the hippocampus that is practically identical to that of long-term potentiation (LTP) in that area. Recent findings have indeed described CA1 LTP concomitant to the consolidation of this and other tasks. However, abundant evidence suggests that, in addition, other molecular events, involving some of the same steps but with different timing and in different sequence in the basolateral amygdala, entorhinal, parietal and cingulate cortex are as important as those of the hippocampus for memory consolidation. Here we review the hippocampal mechanisms involved and the possible interconnections between all these processes. Overall, the findings indicate that memory consolidation of even a task as deceivingly simple as one-trial avoidance relies on hippocampal LTP but also requires the concomitant participation of other brain systems and molecular events. Further, they point to the mechanisms that account for the enhanced consolidation usually seen for emotion-laden memories.

  15. Double dissociation of hippocampal and dorsal-striatal memory systems by posttraining intracerebral injections of 2-amino-5-phosphonopentanoic acid.

    PubMed

    Packard, M G; Teather, L A

    1997-06-01

    Rats received an 8-trial training session on a spatial or cued task in a water maze, followed by a posttraining intracerebral injection of AP5 or saline. On a retention test 24 hr later, latency to mount the escape platform was used as a measure of memory. Intrahippocampal (10 micrograms), but not intra-dorsal striatal (2, 5, or 10 micrograms), injection of AP5 impaired memory in the spatial task. In contrast, intra-dorsal striatal (2 micrograms), but not intrahippocampal (2, 5, or 10 micrograms) injection of AP5 impaired memory in the cued task. Intracerebral injections of AP5 delayed 2 hr posttraining were ineffective. The findings indicate a double dissociation of the roles of the hippocampus and dorsal striatum in memory, a role for N-methyl-D-aspartate receptor function in posttraining memory processes, and a glutamatergic modulation of both hippocampal and dorsal striatal memory processes, suggesting that different forms of memory may share a similar neurochemical basis.

  16. MPTP Impairs Dopamine D1 Receptor-Mediated Survival of Newborn Neurons in Ventral Hippocampus to Cause Depressive-Like Behaviors in Adult Mice

    PubMed Central

    Zhang, Tingting; Hong, Juan; Di, Tingting; Chen, Ling

    2016-01-01

    Parkinson’s disease (PD) is characterized by motor symptoms with depression. We evaluated the influence of dopaminergic depletion on hippocampal neurogenesis process to explore mechanisms of depression production. Five consecutive days of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) injection in mice (MPTP-mice) reduced dopaminergic fibers in hippocampal dentate gyrus (DG). MPTP-mice exhibited depressive-like behaviors later for 2–3 weeks. BrdU was injected 4 h after last-injection of MPTP. BrdU-positive (BrdU+) cells in dorsal (d-DG) and ventral (v-DG) DG were examined on day 1 (D1), 7 (D7), 14 (D14) and 21 (D21) after BrdU injection. Fewer D7-, D14- and D21-BrdU+ cells or BrdU+/NeuN+ cells, but not D1-BrdU+ cells, were found in v-DG of MPTP-mice than in controls. However, the number of BrdU+ cells in d-DG did not differ between the both. Loss of doublecortin-positive (DCX+) cells was observed in v-DG of MPTP-mice. Protein kinase A (PKA) and Ca2+/cAMP-response element binding protein (CREB) phosphorylation were reduced in v-DG of MPTP-mice, which were reversed by D1-like receptor (D1R) agonist SKF38393, but not D2R agonist quinpirole. The treatment of MPTP-mice with SKF38393 on days 2–7 after BrdU-injection reduced the loss of D7- and D21-BrdU+ cells in v-DG and improved the depressive-like behaviors; these changes were sensitive to PKA inhibitor H89. Moreover, the v-DG injection of SKF38393 in MPTP-mice could reduce the loss of D21-BrdU+ cells and relieve the depressive-like behaviors. In control mice, the blockade of D1R by SCH23390 caused the reduction of D21-BrdU+ cells in v-DG and the depressive-like behaviors. Our results indicate that MPTP-reduced dopaminergic depletion impairs the D1R-mediated early survival of newborn neurons in v-DG, producing depressive-like behaviors. PMID:27790091

  17. Encoding, consolidation, and retrieval of contextual memory: Differential involvement of dorsal CA3 and CA1 hippocampal subregions

    PubMed Central

    Daumas, Stéphanie; Halley, Hélène; Francés, Bernard; Lassalle, Jean-Michel

    2005-01-01

    Studies on human and animals shed light on the unique hippocampus contributions to relational memory. However, the particular role of each hippocampal subregion in memory processing is still not clear. Hippocampal computational models and theories have emphasized a unique function in memory for each hippocampal subregion, with the CA3 area acting as an autoassociative memory network and the CA1 area as a critical output structure. In order to understand the respective roles of the CA3- and CA1-hippocampal areas in the formation of contextual memory, we studied the effects of the reversible inactivation by lidocaine of the CA3 or CA1 areas of the dorsal hippocampus on acquisition, consolidation, and retrieval of a contextual fear conditioning. Whereas infusions of lidocaine never impaired elementary tone conditioning, their effects on contextual conditioning provided interesting clues about the role of these two hippocampal regions. They demonstrated first that the CA3 area is necessary for the rapid elaboration of a unified representation of the context. Secondly, they suggested that the CA1 area is rather involved in the consolidation process of contextual memory. Third, they showed that CA1 or CA3 inactivation during retention test has no effect on contextual fear retrieval when a recognition memory procedure is used. In conclusion, our findings point as evidence that CA1 and CA3 subregions of the dorsal hippocampus play important and different roles in the acquisition and consolidation of contextual fear memory, whereas they are not required for context recognition. PMID:16027176

  18. HDAC inhibition modulates hippocampus-dependent long-term memory for object location in a CBP-dependent manner

    PubMed Central

    Haettig, Jakob; Stefanko, Daniel P.; Multani, Monica L.; Figueroa, Dario X.; McQuown, Susan C.; Wood, Marcelo A.

    2011-01-01

    Transcription of genes required for long-term memory not only involves transcription factors, but also enzymatic protein complexes that modify chromatin structure. Chromatin-modifying enzymes, such as the histone acetyltransferase (HAT) CREB (cyclic-AMP response element binding) binding protein (CBP), are pivotal for the transcriptional regulation required for long-term memory. Several studies have shown that CBP and histone acetylation are necessary for hippocampus-dependent long-term memory and hippocampal long-term potentiation (LTP). Importantly, every genetically modified Cbp mutant mouse exhibits long-term memory impairments in object recognition. However, the role of the hippocampus in object recognition is controversial. To better understand how chromatin-modifying enzymes modulate long-term memory for object recognition, we first examined the role of the hippocampus in retrieval of long-term memory for object recognition or object location. Muscimol inactivation of the dorsal hippocampus prior to retrieval had no effect on long-term memory for object recognition, but completely blocked long-term memory for object location. This was consistent with experiments showing that muscimol inactivation of the hippocampus had no effect on long-term memory for the object itself, supporting the idea that the hippocampus encodes spatial information about an object (such as location or context), whereas cortical areas (such as the perirhinal or insular cortex) encode information about the object itself. Using location-dependent object recognition tasks that engage the hippocampus, we demonstrate that CBP is essential for the modulation of long-term memory via HDAC inhibition. Together, these results indicate that HDAC inhibition modulates memory in the hippocampus via CBP and that different brain regions utilize different chromatin-modifying enzymes to regulate learning and memory. PMID:21224411

  19. Fornix White Matter is Correlated with Resting-State Functional Connectivity of the Thalamus and Hippocampus in Healthy Aging but Not in Mild Cognitive Impairment – A Preliminary Study

    PubMed Central

    Kehoe, Elizabeth G.; Farrell, Dervla; Metzler-Baddeley, Claudia; Lawlor, Brian A.; Kenny, Rose Anne; Lyons, Declan; McNulty, Jonathan P.; Mullins, Paul G.; Coyle, Damien; Bokde, Arun L.

    2015-01-01

    In this study, we wished to examine the relationship between the structural connectivity of the fornix, a white matter (WM) tract in the limbic system, which is affected in amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease, and the resting-state functional connectivity (FC) of two key related subcortical structures, the thalamus, and hippocampus. Twenty-two older healthy controls (HC) and 18 older adults with aMCI underwent multi-modal MRI scanning. The fornix was reconstructed using constrained-spherical deconvolution-based tractography. The FC between the thalamus and hippocampus was calculated using a region-of-interest approach from which the mean time series were exacted and correlated. Diffusion tensor imaging measures of the WM microstructure of the fornix were correlated against the Fisher Z correlation values from the FC analysis. There was no difference between the groups in the fornix WM measures, nor in the resting-state FC of the thalamus and hippocampus. We did however find that the relationship between functional and structural connectivity differed significantly between the groups. In the HCs, there was a significant positive association between linear diffusion (CL) in the fornix and the FC of the thalamus and hippocampus, however, there was no relationship between these measures in the aMCI group. These preliminary findings suggest that in aMCI, the relationship between the functional and structural connectivity of regions of the limbic system may be significantly altered compared to healthy ageing. The combined use of diffusion weighted imaging and functional MRI may advance our understanding of neural network changes in aMCI, and elucidate subtle changes in the relationship between structural and functional brain networks. PMID:25698967

  20. AGE-RELATED IMPAIRMENTS IN MEMORY AND IN CREB AND pCREB EXPRESSION IN HIPPOCAMPUS AND AMYGDALA FOLLOWING INHIBITORY AVOIDANCE TRAINING

    PubMed Central

    Morris, Ken A.; Gold, Paul E.

    2012-01-01

    This experiment examined whether age-related changes in CREB and pCREB contribute to the rapid forgetting seen in aged animals. Young (3-month-old) and aged (24-month-old) Fischer-344 rats received inhibitory avoidance training with a low (0.2 mA, 0.4 sec) or moderate (0.5 mA, 0.5 sec) footshock; memory was measured 7 days later. Other rats were euthanized 30 minutes after training, and CREB and pCREB expression levels were examined in the hippocampus, amygdala, and piriform cortex using immunohistochemistry. CREB levels decreased with age in the hippocampus and amygdala. After training with either shock level, young rats exhibited good memory and increases in pCREB levels in the hippocampus and amygdala. Aged rats exhibited good memory for the moderate but not the low shock but did not show increases in pCREB levels after either shock intensity. These results suggest that decreases in total CREB and in pCREB activation in the hippocampus and amygdala may contribute to rapid forgetting in aged rats. After moderate footshock, the stable memory in old rats together with absence of CREB activation suggests either that CREB was phosphorylated in a spatiotemporal pattern other than analyzed here or that the stronger training conditions engaged alternate mechanisms that promote long-lasting memory. PMID:22445851

  1. MTHFR deficiency or reduced intake of folate or choline in pregnant mice results in impaired short-term memory and increased apoptosis in the hippocampus of wild-type offspring.

    PubMed

    Jadavji, N M; Deng, L; Malysheva, O; Caudill, M A; Rozen, R

    2015-08-06

    Genetic or nutritional disturbances in one-carbon metabolism, with associated hyperhomocysteinemia, can result in complex disorders including pregnancy complications and neuropsychiatric diseases. In earlier work, we showed that mice with a complete deficiency of methylenetetrahydrofolate reductase (MTHFR), a critical enzyme in folate and homocysteine metabolism, had cognitive impairment with disturbances in choline metabolism. Maternal demands for folate and choline are increased during pregnancy and deficiencies of these nutrients result in several negative outcomes including increased resorption and delayed development. The goal of this study was to investigate the behavioral and neurobiological impact of a maternal genetic deficiency in MTHFR or maternal nutritional deficiency of folate or choline during pregnancy on 3-week-old Mthfr(+/+) offspring. Mthfr(+/+) and Mthfr(+/-) females were placed on control diets (CD); and Mthfr(+/+) females were placed on folate-deficient diets (FD) or choline-deficient diets (ChDD) throughout pregnancy and lactation until their offspring were 3weeks of age. Short-term memory was assessed in offspring, and hippocampal tissue was evaluated for morphological changes, apoptosis, proliferation and choline metabolism. Maternal MTHFR deficiency resulted in short-term memory impairment in offspring. These dams had elevated levels of plasma homocysteine when compared with wild-type dams. There were no differences in plasma homocysteine in offspring. Increased apoptosis and proliferation was observed in the hippocampus of offspring from Mthfr(+/-) mothers. In the maternal FD and ChDD study, offspring also showed short-term memory impairment with increased apoptosis in the hippocampus; increased neurogenesis was observed in ChDD offspring. Choline acetyltransferase protein was increased in the offspring hippocampus of both dietary groups and betaine was decreased in the hippocampus of FD offspring. Our results reveal short-term memory

  2. Chronic Monoarthritis Pain Accelerates the Processes of Cognitive Impairment and Increases the NMDAR Subunits NR2B in CA3 of Hippocampus from 5-month-old Transgenic APP/PS1 Mice.

    PubMed

    Gong, Wei-Yi; Wang, Rong; Liu, Yuan; Jin, He; Zhao, Zhi-Wei; Wang, Yu-Lan; Li, Hong-Yan; Zhang, Xu; Ni, Jia-Xiang

    2017-01-01

    Many factors impact cognitive impairment; however, the effects of chronic pain and the mechanisms underlying these effects on cognitive impairment are currently unknown. Here we tested the hypothesis that chronic pain accelerates the transition from normal cognition to mild cognitive impairment (MCI) in 5-month-old transgenic APP/PS1 mice, an animal model of Alzheimer's disease (AD), and that neurotoxicity induced by N-methyl-D-aspartic acid receptor (NMDAR) subunits may be involved in this process. Chronic monoarthritis pain was induced in transgenic APP/PS1 mice and 5-month-old wild-type (WT) mice by intra- and pre-articular injections of Freund's complete adjuvant (FCA) into one knee joint. Pain behavior, learning and memory function, and the distribution and quantity of NMDAR subunits (NR1, NR2A and NR2B) in hippocampal CA1 and CA3 regions were assessed. Our results showed that although persistent and robust monoarthritis pain was induced by the FCA injections, only the transgenic APP/PS1 mice with chronic monoarthritis pain exhibited marked learning and memory impairments. This result suggested that chronic monoarthritis pain accelerated the cognitive impairment process. Furthermore, only transgenic APP/PS1 mice with chronic monoarthritis pain exhibited an overexpression of NR2B and an increased NR2B/NR2A ratio in the hippocampus CA3. These findings suggest that chronic pain is a risk factor for cognitive impairment and that increased neurotoxicity associated with NMDAR subunit activation may underpin the impairment. Thus, NMDARs may be a therapeutic target for the prevention of chronic pain-induced cognitive impairment.

  3. Performance in hippocampus- and PFC-dependent cognitive domains are not concomitantly impaired in rats exposed to 20 cGy of 1 GeV/n 56Fe particles

    NASA Astrophysics Data System (ADS)

    Britten, Richard A.; Miller, Vania D.; Hadley, Melissa M.; Jewell, Jessica S.; Macadat, Evangeline

    2016-08-01

    NASA is currently conducting ground based experiments to determine whether the radiation environment that astronauts will encounter on deep space missions will have an impact on their long-term health and their ability to complete the various tasks during the mission. Emerging data suggest that exposure of rodents to mission-relevant HZE radiation doses does result in the impairment of various neurocognitive processes. An essential part of mission planning is a probabilistic risk assessment process that takes into account the likely incidence and severity of a problem. To date few studies have reported the impact of space radiation in a format that is amenable to PRA, and those that have only reported data for a single cognitive process. This study has established the ability of individual male Wistar rats to conduct a hippocampus-dependent (spatial memory) task and a cortex-dependent (attentional set shifting task) 90 days after exposure to 20 cGy 1 GeV/n 56Fe particles. Radiation-induced impairment of performance in one cognitive domain was not consistently associated with impaired performance in the other domain. Thus sole reliance upon a single measure of cognitive performance may substantially under-estimate the risk of cognitive impairment, and ultimately it may be necessary to establish the likelihood that mission-relevant HZE doses will impair performance in the three or four cognitive domains that NASA considers to be most critical for mission success, and build a PRA using the composite data from such studies.

  4. Muscarinic receptors activity in the perirhinal cortex and hippocampus has differential involvement in the formation of recognition memory.

    PubMed

    Balderas, Israela; Morin, Jean-Pascal; Rodriguez-Ortiz, Carlos J; Bermudez-Rattoni, Federico

    2012-05-01

    In this work we probed the effects of post-trial infusions of the muscarinic receptor antagonist scopolamine on object recognition memory formation. Scopolamine was infused bilaterally immediately after the sample phase in the perirhinal cortex or dorsal hippocampus and animals were tested for short-term (90 min) or long-term (24 h) memory. Results showed that scopolamine impaired short-term memory when injected in either the perirhinal cortex or hippocampus. Nevertheless, scopolamine disrupted long-term memory when administrated in the perirhinal cortex but not when applied in the hippocampus. Long-term memory was unaffected when scopolamine was infused 160 min after the sample phase or 90 min before test phase. Our data indicate that short-term recognition memory requires muscarinic receptors signaling in both the perirhinal cortex and hippocampus, whereas long-term recognition memory depends on muscarinic receptors in the perirhinal cortex but not hippocampus. These results support a differential involvement of muscarinic activity in these two medial temporal lobe structures in the formation of recognition memory. Copyright © 2012 Elsevier Inc. All rights reserved.

  5. Transient impairment of hippocampus-dependent learning and memory in relatively low-dose of acute radiation syndrome is associated with inhibition of hippocampal neurogenesis.

    PubMed

    Kim, Joong-Sun; Lee, Hae-June; Kim, Jong Choon; Kang, Seong Soo; Bae, Chun-Sik; Shin, Taekyun; Jin, Jae-Kwang; Kim, Sung Ho; Wang, Hongbing; Moon, Changjong

    2008-09-01

    Neurogenesis in the adult hippocampus, which occurs constitutively, is vulnerable to ionizing radiation. In the relatively low-dose exposure of acute radiation syndrome (ARS), the change in the adult hippocampal function is poorly understood. This study analyzed the changes in apoptotic cell death and neurogenesis in the DGs of hippocampi from adult ICR mice with single whole-body gamma-irradiation using the TUNEL method and immunohistochemical markers of neurogenesis, Ki-67 and doublecortin (DCX). In addition, the hippocampus-dependent learning and memory tasks after single whole-body gamma-irradiation were examined in order to evaluate the hippocampus-related behavioral dysfunction in the relatively low-dose exposure of ARS. The number of TUNEL-positive apoptotic nuclei in the dentate gyrus (DG) was increased 6-12 h after acute gamma-irradiation (a single dose of 0.5 to 4 Gy). In contrast, the number of Ki-67- and DCX-positive cells began to decrease significantly 6 h postirradiation, reaching its lowest level 24 h after irradiation. The level of Ki-67 and DCX immunoreactivity decreased in a dose-dependent manner within the range of irradiation applied (0-4 Gy). In passive avoidance and object recognition memory test, the mice trained 1 day after acute irradiation (2 Gy) showed significant memory deficits, compared with the sham controls. In conclusion, the pattern of the hippocampus-dependent memory dysfunction is consistent with the change in neurogenesis after acute irradiation. It is suggested that a relatively low dose of ARS in adult ICR mice is sufficiently detrimental to interrupt the functioning of the hippocampus, including learning and memory, possibly through the inhibition of neurogenesis.

  6. The hippocampus plays a role in the recognition of visual scenes presented at behaviorally relevant points in time: evidence from amnestic mild cognitive impairment (aMCI) and healthy controls.

    PubMed

    Szamosi, András; Levy-Gigi, Einat; Kelemen, Oguz; Kéri, Szabolcs

    2013-01-01

    When people perform an attentionally demanding target task at fixation, they also encode the surrounding visual environment, which serves as a context of the task. Here, we examined the role of the hippocampus in memory for target and context. Thirty-five patients with amnestic mild cognitive impairment (aMCI) and 35 healthy controls matched for age, gender, and education participated in the study. Participants completed visual letter detection and auditory tone discrimination target tasks, while also viewing a series of briefly presented urban and natural scenes. For the measurement of hippocampal and cerebral cortical volume, we utilized the FreeSurfer protocol using a Siemens Trio 3 T scanner. Before the quantification of brain volumes, hippocampal atrophy was confirmed by visual inspection in each patient. Results revealed intact letter recall and tone discrimination performances in aMCI patients, whereas they showed severe impairments in the recognition of scenes presented together with the targets. Patients with aMCI showed bilaterally reduced hippocampal volumes, but intact cortical volume, as compared with the controls. In controls and in the whole sample, hippocampal volume was positively associated with scene recognition when a target task was present. This relationship was observed in both visual and auditory conditions. Scene recognition and target tasks were not associated with executive functions. These results suggest that the hippocampus plays an essential role in the formation of memory traces of the visual environment when people concurrently perform a target task at behaviorally relevant points in time.

  7. On the delay-dependent involvement of the hippocampus in object recognition memory.

    PubMed

    Hammond, Rebecca S; Tull, Laura E; Stackman, Robert W

    2004-07-01

    The role of the hippocampus in object recognition memory processes is unclear in the current literature. Conflicting results have been found in lesion studies of both primates and rodents. Procedural differences between studies, such as retention interval, may explain these discrepancies. In the present study, acute lidocaine administration was used to temporarily inactivate the hippocampus prior to training in the spontaneous object recognition task. Male C57BL/6J mice were administered bilateral lidocaine (4%, 0.5 microl/side) or aCSF (0.5 microl/side) directly into the CA1 region of the dorsal hippocampus 5 min prior to sample object training, and object recognition memory was tested after a short ( 5 min) or long (24 h) retention interval. There was no effect of intra-hippocampal lidocaine on the time needed for mice to accumulate sample object exploration, suggesting that inactivation of the hippocampus did not affect sample session activity or the motivation to explore objects. Lidocaine-treated mice exhibited impaired object recognition memory, measured as reduced novel object preference, after a 24 h but not a 5 min retention interval. These data support a delay-dependent role for the hippocampus in object recognition memory, an effect consistent with the results of hippocampal lesion studies conducted in rats. However, these data are also consistent with the view that the hippocampus is involved in object recognition memory regardless of retention interval, and that object recognition processes of parahippocampal structures (e.g., perirhinal cortex) are sufficient to support object recognition memory over short retention intervals.

  8. Complementary Roles of the Hippocampus and the Dorsomedial Striatum during Spatial and Sequence-Based Navigation Behavior

    PubMed Central

    Watilliaux, Aurélie; Bontempi, Bruno; Rondi-Reig, Laure

    2013-01-01

    We investigated the neural bases of navigation based on spatial or sequential egocentric representation during the completion of the starmaze, a complex goal-directed navigation task. In this maze, mice had to swim along a path composed of three choice points to find a hidden platform. As reported previously, this task can be solved by using two hippocampal-dependent strategies encoded in parallel i) the allocentric strategy requiring encoding of the contextual information, and ii) the sequential egocentric strategy requiring temporal encoding of a sequence of successive body movements associated to specific choice points. Mice were trained during one day and tested the following day in a single probe trial to reveal which of the two strategies was spontaneously preferred by each animal. Imaging of the activity-dependent gene c-fos revealed that both strategies are supported by an overlapping network involving the dorsal hippocampus, the dorsomedial striatum (DMS) and the medial prefrontal cortex. A significant higher activation of the ventral CA1 subregion was observed when mice used the sequential egocentric strategy. To investigate the potential different roles of the dorsal hippocampus and the DMS in both types of navigation, we performed region-specific excitotoxic lesions of each of these two structures. Dorsal hippocampus lesioned mice were unable to optimally learn the sequence but improved their performances by developing a serial strategy instead. DMS lesioned mice were severely impaired, failing to learn the task. Our data support the view that the hippocampus organizes information into a spatio-temporal representation, which can then be used by the DMS to perform goal-directed navigation. PMID:23826243

  9. Trial-unique, delayed nonmatching-to-location (TUNL) touchscreen testing for mice: sensitivity to dorsal hippocampal dysfunction.

    PubMed

    Kim, Chi Hun; Romberg, Carola; Hvoslef-Eide, Martha; Oomen, Charlotte A; Mar, Adam C; Heath, Christopher J; Berthiaume, Andrée-Anne; Bussey, Timothy J; Saksida, Lisa M

    2015-11-01

    The hippocampus is implicated in many of the cognitive impairments observed in conditions such as Alzheimer's disease (AD) and schizophrenia (SCZ). Often, mice are the species of choice for models of these diseases and the study of the relationship between brain and behaviour more generally. Thus, automated and efficient hippocampal-sensitive cognitive tests for the mouse are important for developing therapeutic targets for these diseases, and understanding brain-behaviour relationships. One promising option is to adapt the touchscreen-based trial-unique nonmatching-to-location (TUNL) task that has been shown to be sensitive to hippocampal dysfunction in the rat. This study aims to adapt the TUNL task for use in mice and to test for hippocampus-dependency of the task. TUNL training protocols were altered such that C57BL/6 mice were able to acquire the task. Following acquisition, dysfunction of the dorsal hippocampus (dHp) was induced using a fibre-sparing excitotoxin, and the effects of manipulation of several task parameters were examined. Mice could acquire the TUNL task using training optimised for the mouse (experiments 1). TUNL was found to be sensitive to dHp dysfunction in the mouse (experiments 2, 3 and 4). In addition, we observed that performance of dHp dysfunction group was somewhat consistently lower when sample locations were presented in the centre of the screen. This study opens up the possibility of testing both mouse and rat models on this flexible and hippocampus-sensitive touchscreen task.

  10. Glucocorticoid receptor deletion from the dorsal raphé nucleus of mice reduces dysphoria-like behavior and impairs hypothalamic-pituitary-adrenocortical axis feedback inhibition.

    PubMed

    Vincent, Melanie Y; Jacobson, Lauren

    2014-05-01

    Glucocorticoids can cause depression and anxiety. Mechanisms for glucocorticoid effects on mood are largely undefined. The dorsal raphé nucleus (DRN) produces the majority of serotonin in the brain, and expresses glucocorticoid receptors (GR). Because we previously showed that antidepressants used to treat depression and anxiety decrease DRN GR expression, we hypothesized that deleting DRN GR would have anxiolytic- and antidepressant-like effects. We also hypothesized that DRN GR deletion would disinhibit activity of the hypothalamic-pituitary-adrenal (HPA) axis. Adeno-associated virus pseudotype AAV2/9 expressing either Cre recombinase (DRNGRKO mice) or GFP (DRN-GFP mice) was injected into the DRN of floxed GR mice to test these hypotheses. Three weeks after injection, mice underwent 21 days of social defeat or control handling and were tested for anxiety-like behavior (open-field test, elevated-plus maze), depression-like behavior [sucrose preference, forced-swim test (FST), tail-suspension test (TST)], social interaction, and circadian and stress-induced HPA activity. DRN GR deletion decreased anxiety-like behavior in control but not in defeated mice. DRN GR deletion decreased FST and tended to decrease TST despair-like behavior in both control and defeated mice, but did not affect sucrose preference. Exploration of social (a novel mouse) as well as neutral (an empty box) targets was increased in DRNGRKO mice, suggesting that DRN GR deletion also promotes active coping. DRN GR deletion increased stress-induced HPA activity without strongly altering circadian HPA activity. We have shown a novel role for DRN GR to mediate anxiety- and despair-like behavior and to regulate HPA negative feedback during acute stress.

  11. Glucocorticoid receptor deletion from the dorsal raphé nucleus of mice reduces dysphoria-like behavior and impairs hypothalamic-pituitary-adrenocortical axis feedback inhibition

    PubMed Central

    Vincent, Melanie Y.; Jacobson, Lauren

    2014-01-01

    Glucocorticoids can cause depression and anxiety. Mechanisms for glucocorticoid effects on mood are largely undefined. The dorsal raphé nucleus (DRN) produces the majority of serotonin in the brain, and expresses glucocorticoid receptors (GR). Since we previously showed that antidepressants used to treat depression and anxiety decrease DRN GR expression, we hypothesized that deleting DRN GR would have anxiolytic- and antidepressant-like effects. We also hypothesized that DRN GR deletion would disinhibit activity of the hypothalamic pituitary adrenal (HPA) axis. Adeno-associated virus pseudotype AAV2/9 expressing either Cre recombinase (DRNGRKO mice) or GFP (DRN-GFP mice) was injected into the DRN of floxed GR mice to test these hypotheses. Three weeks after injection, mice underwent 10d of social defeat or control handling and tested f