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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. 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.

  3. 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

  4. 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.

  5. 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

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. 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…

  19. 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.

  20. 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.

  1. 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.

  2. 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.

  3. 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.

  4. 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

  5. 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.

  6. 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.

  7. 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…

  8. 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

  9. 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.

  10. 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.

  11. 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

  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. 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.

  14. 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.

  15. 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

  16. 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.

  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. 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.

  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. 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

  1. 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

  2. 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.

  3. 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

  4. 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

  5. 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.

  6. 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.

  7. 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.

  8. 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

  9. 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

  10. 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

  11. 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.

  12. 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.

  13. 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

  14. 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.

  15. 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.

  16. 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.

  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. 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.

  19. 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

  20. 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

  1. 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.

  2. 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

  3. 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.

  4. 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.

  5. 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.

  6. 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…

  7. 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.

  8. 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.

  9. 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.

  10. 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

  11. 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.

  12. 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.

  13. 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

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. [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.

  19. [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.

  20. 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.

  1. 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.

  2. 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

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  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. 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

  9. 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.

  10. 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.

  11. 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.

  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.

  13. 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

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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

  20. 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

  1. 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.

  2. 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

  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. 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.

  5. 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

  6. 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.

  7. 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

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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

  14. 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

  15. 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…

  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 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

  17. 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.

  18. 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…

  19. 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.

  20. 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.

  1. 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

  2. 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

  3. 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.

  4. 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.

  5. 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.

  6. 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

  7. 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.

  8. 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.

  9. 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.

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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.

  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. 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.

  17. 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.

  18. 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.

  19. 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

  20. 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.

  1. 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.

  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 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

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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

  8. 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.

  9. 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.

  10. 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

  11. 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

  12. 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.

  13. 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.

  14. 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.

  15. 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

  16. 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.

  17. 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…

  18. 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 ...

  19. 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

  20. 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

  1. 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.

  2. 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.

  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. 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.

  5. 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

  6. 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.

  7. 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

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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'.

  15. 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.

  16. 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

  17. 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.

  18. 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.

  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. 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

  1. 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.

  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. 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

  4. 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.

  5. 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.

  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. 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

  8. 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.

  9. 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

  10. 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.

  11. 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.

  12. 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

  13. 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.

  14. 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.

  15. 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

  16. 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.

  17. 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

    2017-02-20

    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.

  18. 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

  19. 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.

  20. 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

  1. 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

  2. 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

  3. 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.

  4. 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

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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

  15. 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.

  16. 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

  17. 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

  18. 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.

  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

    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.

  20. 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.

  1. 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.

  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. 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.

  4. 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.

  5. ApoE4 expression accelerates hippocampus-dependent cognitive deficits by enhancing Aβ impairment of insulin signaling in an Alzheimer’s disease mouse model

    PubMed Central

    Chan, Elizabeth S.; Shetty, Mahesh Shivarama; Sajikumar, Sreedharan; Chen, Christopher; Soong, Tuck Wah; Wong, Boon-Seng

    2016-01-01

    The apolipoprotein E4 (ApoE4) is the strongest genetic risk factor for Alzheimer’s disease (AD). The AD brain was shown to be insulin resistant at end stage, but the interplay between insulin signaling, ApoE4 and Aβ across time, and their involvement in memory decline is unclear. To investigate insulin response in the ageing mouse hippocampus, we crossed the human ApoE-targeted replacement mice with the mutant human amyloid precursor protein (APP) mice (ApoExAPP). While hippocampal Aβ levels were comparable between ApoE3xAPP and ApoE4xAPP mice at 26 weeks, insulin response was impaired in the ApoE4xAPP hippocampus. Insulin treatment was only able to stimulate insulin signaling and increased AMPA-GluR1 phosphorylation in forskolin pre-treated hippocampal slices from ApoE3xAPP mice. In ApoE4xAPP mice, insulin dysfunction was also associated with poorer spatial memory performance. Using dissociated hippocampal neuron in vitro, we showed that insulin response in ApoE3 and ApoE4 neurons increased AMPA receptor-mediated miniature excitatory postsynaptic current (mEPSC) amplitudes and GluR1-subunit insertion. Pre-treatment of ApoE3 neurons with Aβ42 did not affect insulin-mediated GluR1 subunit insertion. However, impaired insulin sensitivity observed only in the presence of ApoE4 and Aβ42, attenuated GluR1-subunit insertion. Taken together, our results suggest that ApoE4 enhances Aβ inhibition of insulin-stimulated AMPA receptor function, which accelerates memory impairment in ApoE4xAPP mice. PMID:27189808

  6. 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

  7. 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

  8. 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.

  9. 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.

  10. 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

  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.

  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.

  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. 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.

  15. 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.

  16. 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

  17. 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.

  18. 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 ...

  19. 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

  20. 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

  1. 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.

  2. 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.

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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.

  9. 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.

  10. 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.

  11. 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

  12. 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.

  13. 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.

  14. 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.

  15. {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.

  16. 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.

  17. 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.

  18. 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

  19. 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

  20. 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.

  1. 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.

  2. 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.

  3. Decreased Npas4 and Arc mRNA Levels in the Hippocampus of Aged Memory-Impaired Wild-Type But Not Memory Preserved 11β-HSD1 Deficient Mice.

    PubMed

    Qiu, J; Dunbar, D R; Noble, J; Cairns, C; Carter, R; Kelly, V; Chapman, K E; Seckl, J R; Yau, J L W

    2016-01-01

    Mice deficient in the glucocorticoid-regenerating enzyme 11β-HSD1 resist age-related spatial memory impairment. To investigate the mechanisms and pathways involved, we used microarrays to identify differentially expressed hippocampal genes that associate with cognitive ageing and 11β-HSD1. Aged wild-type mice were separated into memory-impaired and unimpaired relative to young controls according to their performance in the Y-maze. All individual aged 11β-HSD1-deficient mice showed intact spatial memory. The majority of differentially expressed hippocampal genes were increased with ageing (e.g. immune/inflammatory response genes) with no genotype differences. However, the neuronal-specific transcription factor, Npas4, and immediate early gene, Arc, were reduced (relative to young) in the hippocampus of memory-impaired but not unimpaired aged wild-type or aged 11β-HSD1-deficient mice. A quantitative reverse transcriptase-polymerase chain reaction and in situ hybridisation confirmed reduced Npas4 and Arc mRNA expression in memory-impaired aged wild-type mice. These findings suggest that 11β-HSD1 may contribute to the decline in Npas4 and Arc mRNA levels associated with memory impairment during ageing, and that decreased activity of synaptic plasticity pathways involving Npas4 and Arc may, in part, underlie the memory deficits seen in cognitively-impaired aged wild-type mice.

  4. 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

  5. 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.

  6. 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

  7. 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.

  8. 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

  9. 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

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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

  15. The hippocampus and flexible spatial knowledge in rats.

    PubMed

    Ramos, J M; Vaquero, J M

    2000-12-01

    Lesions to the hippocampal system in rats result in a profound impairment of place or locale spatial learning although other learning strategies remain unaltered. The main objective of the present study was to investigate whether the spatial knowledge preserved in the hippocampal animals can be expressed flexibly under conditions different from those of the acquisition period. Rats with neurotoxic lesions to the dorsal hippocampus and sham-operated subjects were trained to reach the goal arm in a four-arm plus-shaped maze using a constant starting arm. During the training a transparent plexiglas barrier divided the maze in two equal halves in such a way that the animals could only travel from the starting arm to the goal arm, not having access to the remaining 50% of the maze. After seven days of training, a transfer test was used in which the starting arms were the two arms from which the animals had not started during the training phase. Results indicated that the lesioned rats made significantly more errors than the control subjects. But the most interesting results revealed that the kind of error made by the lesioned animals was congruent with the turn that they had to make during the acquisition phase in order to access the goal arm (reinforced). These results suggest that when the hippocampus is damaged a preserved highly inflexible egocentric strategy is employed to solve the spatial problem.

  16. Chronic unpredictable stress before pregnancy reduce the expression of brain-derived neurotrophic factor and N-methyl-D-aspartate receptor in hippocampus of offspring rats associated with impairment of memory.

    PubMed

    Huang, Yuejun; Shi, Xuechuan; Xu, Hongwu; Yang, Hanhua; Chen, Tian; Chen, Sihong; Chen, Xiaodong

    2010-07-01

    study, pregestational stress can increase serum corticosterone levels and reduce the expression of BDNF and NR2B in the hippocampus of offspring. These alterations are associated with impairment of memory in the adult offspring. These data suggest that, stress before pregnancy might have a profound influence on brain development of offspring, that may persist into and be manifested in adulthood.

  17. Gene expression analysis indicates CB1 receptor upregulation in the hippocampus and neurotoxic effects in the frontal cortex 3 weeks after single-dose MDMA administration in Dark Agouti rats

    PubMed Central

    2013-01-01

    Background 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") is a widely used recreational drug known to impair cognitive functions on the long-run. Both hippocampal and frontal cortical regions have well established roles in behavior, memory formation and other cognitive tasks and damage of these regions is associated with altered behavior and cognitive functions, impairments frequently described in heavy MDMA users. The aim of this study was to examine the hippocampus, frontal cortex and dorsal raphe of Dark Agouti rats with gene expression arrays (Illumina RatRef bead arrays) looking for possible mechanisms and new candidates contributing to the effects of a single dose of MDMA (15 mg/kg) 3 weeks earlier. Results The number of differentially expressed genes in the hippocampus, frontal cortex and the dorsal raphe were 481, 155, and 15, respectively. Gene set enrichment analysis of the microarray data revealed reduced expression of 'memory’ and 'cognition’, 'dendrite development’ and 'regulation of synaptic plasticity’ gene sets in the hippocampus, parallel to the upregulation of the CB1 cannabinoid- and Epha4, Epha5, Epha6 ephrin receptors. Downregulated gene sets in the frontal cortex were related to protein synthesis, chromatin organization, transmembrane transport processes, while 'dendrite development’, 'regulation of synaptic plasticity’ and 'positive regulation of synapse assembly’ gene sets were upregulated. Changes in the dorsal raphe region were mild and in most cases not significant. Conclusion The present data raise the possibility of new synapse formation/synaptic reorganization in the frontal cortex three weeks after a single neurotoxic dose of MDMA. In contrast, a prolonged depression of new neurite formation in the hippocampus is suggested by the data, which underlines the particular vulnerability of this brain region after the drug treatment. Finally, our results also suggest the substantial contribution of CB1 receptor and

  18. Fibromyalgia Patients Had Normal Distraction Related Pain Inhibition but Cognitive Impairment Reflected in Caudate Nucleus and Hippocampus during the Stroop Color Word Test

    PubMed Central

    Martinsen, Sofia; Flodin, Pär; Berrebi, Jonathan; Löfgren, Monika; Bileviciute-Ljungar, Indre; Ingvar, Martin; Fransson, Peter; Kosek, Eva

    2014-01-01

    The mechanisms causing cognitive problems in chronic pain patients are not well understood. We used the Stroop color word task (SCWT) to investigate distraction-induced analgesia, cognitive performance, and cerebral activation patterns in 29 fibromyalgia (FM) patients (mean age 49.8 years, range 25–64 years) and 31 healthy controls (HC) (mean age 46.3 years, range 20–63 years). In the first study, SCWT was used to investigate distraction-induced analgesia in FM patients. Two versions of the task were applied, one with only congruent color-word images and one with incongruent images. Pressure pain thresholds were assessed using a pressure algometer before, during, and following SCWT. In the second study, reaction times (RTs) were assessed and functional magnetic resonance imaging (fMRI) was used to investigate cerebral activation patterns in FM patients and HC during the SCWT. An event-related task mixing incongruent and congruent images was used. In study one, we found reduced pressure pain sensitivity during SCWT in both groups alike and no statistically significant differences were seen between the incongruent and congruent conditions. The study two revealed longer RTs during the incongruent compared to the congruent condition in both groups. FM patients had longer RTs than HC in both conditions. Furthermore, we found a significant interaction between group and congruency; that is, the group differences in RTs were more pronounced during the incongruent condition. This was reflected in a reduced activation of the caudate nucleus, lingual gyrus, temporal areas, and the hippocampus in FM patients compared to HC. In conclusion, we found normal pain inhibition during SWTC in FM patients. The cognitive difficulties seen in FM patients, reflected in longer RTs, were related to reduced activation of the caudate nucleus and hippocampus during incongruent SCWT, which most likely affected the mechanisms of cognitive learning in FM patients. PMID:25275449

  19. Polychlorinated biphenyls impair blood-brain barrier integrity via disruption of tight junction proteins in cerebrum, cerebellum and hippocampus of female Wistar rats: neuropotential role of quercetin.

    PubMed

    Selvakumar, K; Prabha, R Lakshmi; Saranya, K; Bavithra, S; Krishnamoorthy, G; Arunakaran, J

    2013-07-01

    Polychlorinated biphenyls (PCBs) comprise a ubiquitous class of toxic substances associated with carcinogenic and tumor-promoting effects as well as neurotoxic properties. Reactive oxygen species, which is produced from PCBs, alters blood-brain barrier (BBB) integrity, which is paralleled by cytoskeletal rearrangements and redistribution and disappearance of tight junction proteins (TJPs) like claudin-5 and occludin. Quercetin, a potent antioxidant present in onion and other vegetables, appears to protect brain cells against oxidative stress, a tissue-damaging process associated with Alzheimer's and other neurodegenerative disorders. The aim of this study is to analyze the role of quercetin on oxidative stress markers and transcription of transmembrane and cytoplasmic accessory TJPs on cerebrum, cerebellum and hippocampus of female rats exposed to PCBs. Rats were divided into the following four groups. Group I: received only vehicle (corn oil) intraperitoneally (i.p.); group II: received Aroclor 1254 at a dose of 2 mg/kg body weight (bwt)/day (i.p); group III: received Aroclor 1254 (i.p.) and simultaneously quercetin 50 mg/kg bwt/day through gavage and group IV: received quercetin alone gavage. From the experiment, the levels of hydrogen peroxide, lipid peroxidation and thiobarbituric acid reactive substances were observed to increase significantly in cerebrum, cerebellum and hippocampus as 50%, 25% and 20%, respectively, after exposure to PCB, and the messenger RNA expression of TJP in rats exposed to PCBs is decreased and is retrieved to the normal level simultaneously in quercetin-treated rats. Hence, quercetin can be used as a preventive medicine to PCBs exposure and prevents neurodegenerative disorders.

  20. Hippocampal Infusion of Zeta Inhibitory Peptide Impairs Recent, but Not Remote, Recognition Memory in Rats

    PubMed Central

    Hales, Jena B.; Ocampo, Amber C.; Broadbent, Nicola J.; Clark, Robert E.

    2015-01-01

    Spatial memory in rodents can be erased following the infusion of zeta inhibitory peptide (ZIP) into the dorsal hippocampus via indwelling guide cannulas. It is believed that ZIP impairs spatial memory by reversing established late-phase long-term potentiation (LTP). However, it is unclear whether other forms of hippocampus-dependent memory, such as recognition memory, are also supported by hippocampal LTP. In the current study, we tested recognition memory in rats following hippocampal ZIP infusion. In order to combat the limited targeting of infusions via cannula, we implemented a stereotaxic approach for infusing ZIP throughout the dorsal, intermediate, and ventral hippocampus. Rats infused with ZIP 3–7 days after training on the novel object recognition task exhibited impaired object recognition memory compared to control rats (those infused with aCSF). In contrast, rats infused with ZIP 1 month after training performed similar to control rats. The ability to form new memories after ZIP infusions remained intact. We suggest that enhanced recognition memory for recent events is supported by hippocampal LTP, which can be reversed by hippocampal ZIP infusion. PMID:26380123

  1. The Effects of Sesquiterpenes-Rich Extract of Alpinia oxyphylla Miq. on Amyloid-β-Induced Cognitive Impairment and Neuronal Abnormalities in the Cortex and Hippocampus of Mice

    PubMed Central

    Shi, Shao-Huai; Zhao, Xu; Liu, Bing; Li, Huan; Liu, Ai-Jing; Wu, Bo; Bi, Kai-Shun

    2014-01-01

    As a kind of medicine which can also be used as food, Alpinia oxyphylla Miq. has a long clinical history in China. A variety of studies demonstrated the significant neuroprotective activity effects of chloroform (CF) extract from the fruits of Alpinia oxyphylla. In order to further elucidate the possible mechanisms of CF extract which mainly contains sesquiterpenes with neuroprotection on the cognitive ability, mice were injected with Aβ1−42 and later with CF in this study. The results showed that the long-term treatment of CF enhanced the cognitive performances in behavior tests, increased activities of glutathione peroxidase (GSH-px) and decreased the level of malondialdehyde (MDA), acetylcholinesterase (AChE), and amyloid-β (Aβ), and reversed the activation of microglia, degeneration of neuronal acidophilia, and nuclear condensation in the cortex and hippocampus. These results demonstrate that CF ameliorates learning and memory deficits by attenuating oxidative stress and regulating the activation of microglia and degeneration of neuronal acidophilia to reinforce cholinergic functions. PMID:25180067

  2. Increasing SK2 channel activity impairs associative learning

    PubMed Central

    McKay, Bridget M.; Oh, M. Matthew; Galvez, Roberto; Burgdorf, Jeffrey; Kroes, Roger A.; Weiss, Craig; Adelman, John P.; Moskal, Joseph R.

    2012-01-01

    Enhanced intrinsic neuronal excitability of hippocampal pyramidal neurons via reductions in the postburst afterhyperpolarization (AHP) has been hypothesized to be a biomarker of successful learning. This is supported by considerable evidence that pharmacologic enhancement of neuronal excitability facilitates learning. However, it has yet to be demonstrated that pharmacologic reduction of neuronal excitability restricted to the hippocampus can retard acquisition of a hippocampus-dependent task. Thus, the present study was designed to address this latter point using a small conductance potassium (SK) channel activator NS309 focally applied to the dorsal hippocampus. SK channels are important contributors to intrinsic excitability, as measured by the medium postburst AHP. NS309 increased the medium AHP and reduced excitatory postsynaptic potential width of CA1 neurons in vitro. In vivo, NS309 reduced the spontaneous firing rate of CA1 pyramidal neurons and impaired trace eyeblink conditioning in rats. Conversely, trace eyeblink conditioning reduced levels of SK2 channel mRNA and protein in the hippocampus. Therefore, the present findings indicate that modulation of SK channels is an important cellular mechanism for associative learning and further support postburst AHP reductions in hippocampal pyramidal neurons as a biomarker of successful learning. PMID:22552186

  3. Hippocampal CB(1) receptors mediate the memory impairing effects of Delta(9)-tetrahydrocannabinol.

    PubMed

    Wise, Laura E; Thorpe, Andrew J; Lichtman, Aron H

    2009-08-01

    It is firmly established that the hippocampus, a brain region implicated in spatial learning, episodic memory, and consolidation, contains a high concentration of CB(1) receptors. Moreover, systemic and intrahippocampal administration of cannabinoid agonists have been shown to impair hippocampal-dependent memory tasks. However, the degree to which CB(1) receptors in the hippocampus play a specific functional role in the memory disruptive effects of marijuana or its primary psychoactive constituent Delta(9)-tetrahydrocannabinol (Delta(9)-THC) is unknown. This study was designed to determine whether hippocampal CB(1) receptors play a functional role in the memory disruptive effects of systemically administered cannabinoids, using the radial arm maze, a well characterized rodent model of working memory. Male Sprague-Dawley rats were implanted with bilateral cannulae aimed at the CA1 region of the dorsal hippocampus. The CB(1) receptor antagonist, rimonabant, was delivered into the hippocampus before to a systemic injection of either Delta(9)-THC or the potent cannabinoid analog, CP-55,940. Strikingly, intrahippocampal administration of rimonabant completely attenuated the memory disruptive effects of both cannabinoids in the radial arm maze task, but did not affect other pharmacological properties of cannabinoids, as assessed in the tetrad assay (that is, hypomotility, analgesia, catalepsy, and hypothermia). Infusions of rimonabant just dorsal or ventral to the hippocampus did not prevent Delta(9)-THC-induced memory impairment, indicating that its effects on mnemonic function were regionally selective. These findings provide compelling evidence in support of the view that hippocampal CB(1) receptors play a necessary role in the memory disruptive effects of marijuana.

  4. Role of Amygdala and Hippocampus in the Neural Circuit Subserving Conditioned Defeat in Syrian Hamsters

    ERIC Educational Resources Information Center

    Markham, Chris M.; Taylor, Stacie L.; Huhman, Kim L.

    2010-01-01

    We examined the roles of the amygdala and hippocampus in the formation of emotionally relevant memories using an ethological model of conditioned fear termed conditioned defeat (CD). Temporary inactivation of the ventral, but not dorsal hippocampus (VH, DH, respectively) using muscimol disrupted the acquisition of CD, whereas pretraining VH…

  5. Effects of amyloid-β peptides on the serotoninergic 5-HT1A receptors in the rat hippocampus.

    PubMed

    Verdurand, Mathieu; Bérod, Anne; Le Bars, Didier; Zimmer, Luc

    2011-01-01

    A recent [(18)F]MPPF-positron emission tomography study has highlighted an overexpression of 5-HT(1A) receptors in the hippocampus of patients with mild cognitive impairment compared to a decrease in those with Alzheimer's disease (AD) [Truchot, L., Costes, S.N., Zimmer, L., Laurent, B., Le Bars, D., Thomas-Antérion, C., Croisile, B., Mercier, B., Hermier, M., Vighetto, A., Krolak-Salmon, P., 2007. Up-regulation of hippocampal serotonin metabolism in mild cognitive impairment. Neurology 69 (10), 1012-1017]. We used in vivo and in vitro neuroimaging to evaluate the longitudinal effects of injecting amyloid-β (Aβ) peptides (1-40) into the dorsal hippocampus of rats. In vivo microPET imaging showed no significant change in [(18)F]MPPF binding in the dorsal hippocampus over time, perhaps due to spatial resolution. However, in vitro autoradiography with [(18)F]MPPF (which is antagonist) displayed a transient increase in 5-HT(1A) receptor density 7 days after Aβ injection, whereas [(18)F]F15599 (a radiolabelled 5-HT(1A) agonist) binding was unchanged suggesting that the overexpressed 5-HT(1A) receptors were in a non-functional state. Complementary histology revealed a loss of glutamatergic neurons and an intense astroglial reaction at the injection site. Although a neurogenesis process cannot be excluded, we propose that Aβ injection leads to a transient astroglial overexpression of 5-HT(1A) receptors in compensation for the local neuronal loss. Exploration of the functional consequences of these serotoninergic modifications during the neurodegenerative process may have an impact on therapeutics targeting 5-HT(1A) receptors in AD.

  6. Cellular and metabolic alterations in the hippocampus caused by insulin signalling dysfunction and its association with cognitive impairment during aging and Alzheimer's disease: studies in animal models.

    PubMed

    Calvo-Ochoa, Erika; Arias, Clorinda

    2015-01-01

    A growing body of animal and epidemiological studies suggest that metabolic diseases such as obesity, insulin resistance, metabolic syndrome and type 2 diabetes mellitus are associated with the development of cognitive impairment, dementia and Alzheimer's disease, particularly in aging. Several lines of evidence suggest that insulin signalling dysfunction produces these metabolic alterations and underlie the development of these neurodegenerative diseases. In this article, we address normal insulin function in the synapse; we review and discuss the physiopathological hallmarks of synaptic insulin signalling dysfunction associated with metabolic alterations. Additionally, we describe and review the major animal models of obesity, insulin resistance, metabolic syndrome and type 2 diabetes mellitus. The comprehensive knowledge of the molecular mechanisms behind the association of metabolic alterations and cognitive impairment could facilitate the early detection of neurodegenerative diseases in patients with metabolic alterations, with treatment that focus on neuroprotection. It could also help in the development of metabolic-based therapies and drugs for using in dementia and Alzheimer's disease patients to alleviate their symptoms in a more efficient and comprehensive way.

  7. Time course of dorsal and ventral hippocampal involvement in the expression of trace fear conditioning.

    PubMed

    Cox, David; Czerniawski, Jennifer; Ree, Fredrick; Otto, Tim

    2013-11-01

    While a number of early studies demonstrated that hippocampal damage attenuates the expression of recent, but not remotely trained tasks, an emerging body of evidence has shown that damage to, or inactivation of, the hippocampus often impairs recall across a wide range of training-testing intervals. Collectively, these data suggest that the time course of hippocampal involvement in the storage or recall of previously-acquired memories may differ according to hippocampal subregion and the particular learning task under consideration. The present study examined the contributions of dorsal (DH) and ventral (VH) hippocampus to the expression of previously-acquired trace fear conditioning, a form of Pavlovian conditioning in which the offset of an initially neutral cue or cues and the onset of an aversive stimulus is separated by a temporal (trace) interval. Specifically, either saline or the GABA-A agonist muscimol was infused into DH or VH prior to testing either 1, 7, 28, or 42 days after trace fear conditioning. The results revealed a marked dissociation: pre-testing inactivation of DH failed to impair performance at any time-point, while pre-testing inactivation of VH impaired performance at all time-points. Importantly, pre-testing inactivation of VH had no effect on the performance of previously-acquired delay conditioning, suggesting that the deficits observed in trace conditioning cannot be attributed to a deficit in performance of the freezing response. Collectively, these data suggest that VH, but not DH, remains a neuroanatomical locus critical to the recall or expression of trace fear conditioning over an extended period of time.

  8. Dorsal Hippocampus Function in Learning and Expressing a Spatial Discrimination

    ERIC Educational Resources Information Center

    White, Norman M.; Gaskin, Stephane

    2006-01-01

    Learning to discriminate between spatial locations defined by two adjacent arms of a radial maze in the conditioned cue preference paradigm requires two kinds of information: latent spatial learning when the rats explore the maze with no food available, and learning about food availability in two spatial locations when the rats are then confined…

  9. Nutrient restriction during early life reduces cell proliferation in the hippocampus at adulthood but does not impair the neuronal differentiation process of the new generated cells.

    PubMed

    Matos, R J B; Orozco-Solís, R; Lopes de Souza, S; Manhães-de-Castro, R; Bolaños-Jiménez, F

    2011-11-24

    Maternal malnutrition results in learning deficits and predisposition to anxiety and depression in the offspring that extend into adulthood. At the cellular level, learning and memory rely on the production of new neurons in the dentate gyrus (DG) of the hippocampus, and hippocampal neurogenesis has been associated with the etiology and treatment of depression, but whether adult neurogenesis is affected by malnutrition during early life is not known. To investigate the effects of perinatal undernutrition on neurogenesis at adulthood, pregnant Sprague-Dawley rats were fed either ad libitum (C) or were undernourished by reducing their daily food intake by 50% in relation to the C group during gestation and lactation (FR/FR). At birth, one subset of control pups was cross-fostered to food-restricted dams to constitute a third group of animals that were undernourished during the lactation period only (AdLib/FR). At 90 days of age, pups were injected with bromodeoxyuridine (BrdU) and sacrificed 2 h, 1 week, or 3 weeks later. The number of BrdU-labeled cells in the DG was significantly reduced in the offspring of FR/FR dams in relation to controls at all the time points examined. However, the proportion of new cells exhibiting a neuronal phenotype was higher in FR/FR rats than in controls as revealed by the colabeling at 3 weeks of the BrdU-labeled cells with neuron-specific nuclear protein (NeuN). AdLib/FR animals exhibited also reduced BrdU labeling at 2 h and 1 week. Nevertheless, we found no significant differences at 3 weeks in either the number of BrdU-labeled cells or in the proportion of new neurons between controls and AdLib/FR rats. These results indicate that the decreased number of hippocampal neurons in perinatally undernourished rats is due to the deleterious effects of early nutrient restriction on cell proliferation but not on the neuronal differentiation process of the new generated cells.

  10. Maternal trans fat intake during pregnancy or lactation impairs memory and alters BDNF and TrkB levels in the hippocampus of adult offspring exposed to chronic mild stress.

    PubMed

    Pase, Camila Simonetti; Roversi, Karine; Roversi, Katiane; Vey, Luciana Taschetto; Dias, Verônica Tironi; Veit, Juliana Cristiana; Maurer, Luana Haselein; Duarte, Thiago; Emanuelli, Tatiana; Duarte, Marta; Bürger, Marilise Escobar

    2017-02-01

    This study aimed to assess the influence of maternal dietary fat intake during pregnancy or lactation on memory of adult offspring after chronic mild stress (CMS) exposure. Female Wistar rats were supplemented daily with soybean oil/fish oil (SO/FO) or hydrogenated vegetable fat (HVF) by oral gavage (3.0g/kg body weight) during pregnancy or lactation. On post-natal day (PND) 60, half of the animals were exposed to CMS following behavioral assessments. While the adult offspring born under influence of SO/FO and HVF supplementations during pregnancy showed higher levels of n-3 and n-6 fatty acids (FA) series DHA and ARA metabolites, respectively, in the hippocampus, adult offspring born from supplemented dams during lactation showed higher levels of their precursors: ALA and LA. However, only HVF supplementation allowed TFA incorporation of adult offspring, and levels were higher in lactation period. Adult offspring born from dams supplemented with trans fat in both pregnancy and lactation showed short and long-term memory impairments before and after CMS. Furthermore, our study also showed higher memory impairment in offspring born from HVF-supplemented dams during lactation in comparison to pregnancy. BDNF expression was increased by stress exposure in offspring from both SO/FO- and HVF-supplemented dams during pregnancy. In addition, offspring from HVF-supplemented dams showed decreased TrkB expression in both supplemented periods, regardless of stress exposure. In conclusion, these findings show for the first time that the type of dietary FA as well as the period of brain development is able to change FA incorporation in brain neural membranes.

  11. Inactivation of muscarinic receptors impairs place and response learning: implications for multiple memory systems.

    PubMed

    Soares, Juliana Carlota Kramer; Oliveira, Maria Gabriela Menezes; Ferreira, Tatiana Lima

    2013-10-01

    Extensive research has shown that the hippocampus and striatum have dissociable roles in memory and are necessary for place and response learning, respectively. Additional evidence indicates that muscarinic cholinergic receptors in the hippocampus and striatum exert an important role in the modulation of these memory systems. In our experiments, we assessed whether intact hippocampal and striatal muscarinic cholinergic transmission may be essential and/or necessary for place and response learning. We addressed these questions using administration of the muscarinic receptor antagonist, scopolamine, on both place and response learning in a food-rewarded T-maze task. The administration of scopolamine (15 μg or 30 μg) directly into the dorsal hippocampus impaired the performance of rats subjected to both place and cue-rich response version of the task, but did not affect the response version, when the task was performed under cue-poor conditions. However, the administration of scopolamine in the dorsolateral striatum impaired the cue-poor response version of the T-maze task without interfering with the place version or cue-rich response version. Taken together, these results indicate that activation of muscarinic cholinergic receptors in the hippocampus and striatum facilitate the use of different strategies of learning, thus strengthening the hypothesis of multiple memory systems. Additionally, these results emphasize the importance of the environmental conditions under which tasks are performed.

  12. The hippocampus in neurodegenerative disease.

    PubMed

    Moodley, K K; Chan, D

    2014-01-01

    AD is the commonest neurodegenerative disorder resulting ultimately in dementia, a stage during which there is a loss of previously acquired intellectual skill and independent occupational and social function. Neurodegenerative changes within the hippocampus and an extended neuronal network involving the medial temporal and medial parietal lobe result in the archetypal memory impairment seen in Alzheimer's disease (AD). As attention focuses increasingly on early diagnosis and treatment of dementia, this understanding of the hippocampal involvement in AD has helped to develop diagnostic tools for use in early disease. However, hippocampal damage is also a common feature among non-AD neurodegenerative dementias. Neuroimaging techniques, in conjunction with behavioral and pathological techniques, can be used to determine the involvement of the hippocampus in AD and other neurodegenerative diseases.

  13. Glucocorticoids and the ageing hippocampus

    PubMed Central

    HIBBERD, CARINA; YAU, JOYCE L. W.; SECKL, JONATHAN R.

    2000-01-01

    Approximately 30% of human and mammalian populations develop cognitive impairments with ageing. Many of these impairments have been linked to dysfunction of the hippocampus, a well studied area of the medial-temporal lobe, which is involved in episodic memory and control of the hypothalamo-pituitary-adrenal stress axis and, thus, of glucocorticoid secretion. This paper reviews the growing body of studies which explore a possible relationship between lifetime exposure to glucocorticoids and hippocampal impairment. There is now strong evidence which associates hypercortisolemia in aged men with later cognitive dysfunction and this complements a wealth of rodent and other human data. We conclude with a discussion of possible pharmacological and behavioural interventions. PMID:11197528

  14. Rapid effects of dorsal hippocampal G-protein coupled estrogen receptor on learning in female mice.

    PubMed

    Lymer, Jennifer; Robinson, Alana; Winters, Boyer D; Choleris, Elena

    2017-03-01

    Through rapid mechanisms of action, estrogens affect learning and memory processes. It has been shown that 17β-estradiol and an Estrogen Receptor (ER) α agonist enhances performance in social recognition, object recognition, and object placement tasks when administered systemically or infused in the dorsal hippocampus. In contrast, systemic and dorsal hippocampal ERβ activation only promote spatial learning. In addition, 17β-estradiol, the ERα and the G-protein coupled estrogen receptor (GPER) agonists increase dendritic spine density in the CA1 hippocampus. Recently, we have shown that selective systemic activation of the GPER also rapidly facilitated social recognition, object recognition, and object placement learning in female mice. Whether activation the GPER specifically in the dorsal hippocampus can also rapidly improve learning and memory prior to acquisition is unknown. Here, we investigated the rapid effects of infusion of the GPER agonist, G-1 (dose: 50nM, 100nM, 200nM), in the dorsal hippocampus on social recognition, object recognition, and object placement learning tasks in home cage. These paradigms were completed within 40min, which is within the range of rapid estrogenic effects. Dorsal hippocampal administration of G-1 improved social (doses: 50nM, 200nM G-1) and object (dose: 200nM G-1) recognition with no effect on object placement. Additionally, when spatial cues were minimized by testing in a Y-apparatus, G-1 administration promoted social (doses: 100nM, 200nM G-1) and object (doses: 50nM, 100nM, 200nM G-1) recognition. Therefore, like ERα, the GPER in the hippocampus appears to be sufficient for the rapid facilitation of social and object recognition in female mice, but not for the rapid facilitation of object placement learning. Thus, the GPER in the dorsal hippocampus is involved in estrogenic mediation of learning and memory and these effects likely occur through rapid signalling mechanisms.

  15. Adult Onset-hypothyroidism has Minimal Effects on Synaptic Transmission in the Hippocampus of Rats Independent of Hypothermia

    EPA Science Inventory

    Introduction: Thyroid hormones (TH) influence central nervous system (CNS) function during development and in adulthood. The hippocampus, a brain area critical for learning and memory is sensitive to TH insufficiency. Synaptic transmission in the hippocampus is impaired following...

  16. Preconditioning of Spatial and Auditory Cues: Roles of the Hippocampus, Frontal Cortex, and Cue-Directed Attention

    PubMed Central

    Talk, Andrew C.; Grasby, Katrina L.; Rawson, Tim; Ebejer, Jane L.

    2016-01-01

    Loss of function of the hippocampus or frontal cortex is associated with reduced performance on memory tasks, in which subjects are incidentally exposed to cues at specific places in the environment and are subsequently asked to recollect the location at which the cue was experienced. Here, we examined the roles of the rodent hippocampus and frontal cortex in cue-directed attention during encoding of memory for the location of a single incidentally experienced cue. During a spatial sensory preconditioning task, rats explored an elevated platform while an auditory cue was incidentally presented at one corner. The opposite corner acted as an unpaired control location. The rats demonstrated recollection of location by avoiding the paired corner after the auditory cue was in turn paired with shock. Damage to either the dorsal hippocampus or the frontal cortex impaired this memory ability. However, we also found that hippocampal lesions enhanced attention directed towards the cue during the encoding phase, while frontal cortical lesions reduced cue-directed attention. These results suggest that the deficit in spatial sensory preconditioning caused by frontal cortical damage may be mediated by inattention to the location of cues during the latent encoding phase, while deficits following hippocampal damage must be related to other mechanisms such as generation of neural plasticity. PMID:27999366

  17. Dorsal hippocampal NMDA receptors mediate the interactive effects of arachidonylcyclopropylamide and MDMA/ecstasy on memory retrieval in rats.

    PubMed

    Ghaderi, Marzieh; Rezayof, Ameneh; Vousooghi, Nasim; Zarrindast, Mohammad-Reza

    2016-04-03

    A combination of cannabis and ecstasy may change the cognitive functions more than either drug alone. The present study was designed to investigate the possible involvement of dorsal hippocampal NMDA receptors in the interactive effects of arachidonylcyclopropylamide (ACPA) and ecstasy/MDMA on memory retrieval. Adult male Wistar rats were cannulated into the CA1 regions of the dorsal hippocampus (intra-CA1) and memory retrieval was examined using the step-through type of passive avoidance task. Intra-CA1 microinjection of a selective CB1 receptor agonist, ACPA (0.5-4ng/rat) immediately before the testing phase (pre-test), but not after the training phase (post-training), impaired memory retrieval. In addition, pre-test intra-CA1 microinjection of MDMA (0.5-1μg/rat) dose-dependently decreased step-through latency, indicating an amnesic effect of the drug by itself. Interestingly, pre-test microinjection of a higher dose of MDMA into the CA1 regions significantly improved ACPA-induced memory impairment. Moreover, pre-test intra-CA1 microinjection of a selective NMDA receptor antagonist, D-AP5 (1 and 2μg/rat) inhibited the reversal effect of MDMA on the impairment of memory retrieval induced by ACPA. Pre-test intra-CA1 microinjection of the same doses of D-AP5 had no effect on memory retrieval alone. These findings suggest that ACPA or MDMA consumption can induce memory retrieval impairment, while their co-administration improves this amnesic effect through interacting with hippocampal glutamatergic-NMDA receptor mechanism. Thus, it seems that the tendency to abuse cannabis with ecstasy may be for avoiding cognitive dysfunction.

  18. Role of α7- and α4β2-nAChRs in the neuroprotective effect of nicotine in stress-induced impairment of hippocampus-dependent memory.

    PubMed

    Alzoubi, Karem H; Srivareerat, Marisa; Tran, Trinh T; Alkadhi, Karim A

    2013-06-01

    We have previously shown that nicotine prevents stress-induced memory impairment. In this study, we have investigated the role of α7- and α4β2-nicotinic acetylcholine receptors (nAChRs) in the protective effect of nicotine during chronic stress conditions. Chronic psychosocial stress was induced using a form of rat intruder model. During stress, specific antagonist for either α7-nAChRs [methyllycaconitine (MLA)] or α4β2-nAChRs [dihydro-β-erythroidine (DHβE)] was infused into the hippocampus using a 4-wk osmotic pump at a rate of 82 μg/side.d and 41 μg/side.d, respectively. Three weeks after the start of infusion, all rats were subjected to a series of cognitive tests in the radial arm water maze (RAWM) for six consecutive days or until the animal reached days to criterion (DTC) in the fourth acquisition trial and in all memory tests. DTC is defined as the number of days the animal takes to make no more than one error in three consecutive days. In the short-term memory test, MLA-infused stressed/nicotine-treated rats made similar errors to those of stress and significantly more errors compared to those of stress/nicotine, nicotine or control groups. This finding was supported by the DTC values for the short memory tests. Thus, MLA treatment blocked the neuroprotective effect of nicotine during chronic stress. In contrast, DHβE infusion did not affect the RAWM performance of stress/nicotine animals. These results strongly suggest the involvement of α7-nAChRs, but not α4β2-nAChRs, in the neuroprotective effect of chronic nicotine treatment during chronic stress conditions.

  19. Sevoflurane-induced down-regulation of hippocampal oxytocin and arginine vasopressin impairs juvenile social behavioral abilities.

    PubMed

    Zhou, Zhi-Bin; Yang, Xiao-Yu; Yuan, Bao-Long; Niu, Li-Jun; Zhou, Xue; Huang, Wen-Qi; Feng, Xia; Zhou, Li-Hua

    2015-05-01

    Cumulative evidence indicates that early childhood anesthesia can alter a child's future behavioral performance. Animal researchers have found that sevoflurane, the most commonly used anesthetic for children, can produce damage in the neonatal brains of rodents. To further investigate this phenomenon, we focused on the influence of sevoflurane anesthesia on the development of juvenile social behavioral abilities and the pro-social proteins oxytocin (OT) and arginine vasopressin (AVP) in the neonatal hippocampus. A single 6-h sevoflurane exposure for postnatal day 5 mice resulted in decreased OT and AVP messenger RNA (mRNA) and protein levels in the hippocampus. OT and AVP proteins became sparsely distributed in the dorsal hippocampus after the exposure to sevoflurane. Compared with the air-treated group, mice in the sevoflurane-treated group showed signs of impairment in social recognition memory formation and social discrimination ability. Sevoflurane anesthesia reduces OT and AVP activities in the neonatal hippocampus and impairs social recognition memory formation and social discrimination ability in juvenile mice.

  20. Chewing Maintains Hippocampus-Dependent Cognitive Function

    PubMed Central

    Chen, Huayue; Iinuma, Mitsuo; Onozuka, Minoru; Kubo, Kin-Ya

    2015-01-01

    Mastication (chewing) is important not only for food intake, but also for preserving and promoting the general health. Recent studies have showed that mastication helps to maintain cognitive functions in the hippocampus, a central nervous system region vital for spatial memory and learning. The purpose of this paper is to review the recent progress of the association between mastication and the hippocampus-dependent cognitive function. There are multiple neural circuits connecting the masticatory organs and the hippocampus. Both animal and human studies indicated that cognitive functioning is influenced by mastication. Masticatory dysfunction is associated with the hippocampal morphological impairments and the hippocampus-dependent spatial memory deficits, especially in elderly. Mastication is an effective behavior for maintaining the hippocampus-dependent cognitive performance, which deteriorates with aging. Therefore, chewing may represent a useful approach in preserving and promoting the hippocampus-dependent cognitive function in older people. We also discussed several possible mechanisms involved in the interaction between mastication and the hippocampal neurogenesis and the future directions for this unique fascinating research. PMID:26078711

  1. The neurosteroid allopregnanolone impairs object memory and contextual fear memory in male C57BL/6J mice.

    PubMed

    Rabinowitz, Akiva; Cohen, Sarah J; Finn, Deborah A; Stackman, Robert W

    2014-07-01

    Allopregnanolone (ALLO, or 3α-hydroxy-5α-pregnan-20-one) is a steroid metabolite of progesterone and a potent endogenous positive allosteric modulator of GABA-A receptors. Systemic ALLO has been reported to impair spatial, but not nonspatial learning in the Morris water maze (MWM) and contextual memory in rodents. These cognitive effects suggest an influence of ALLO on hippocampal-dependent memory, although the specific nature of the neurosteroid's effects on learning, memory or performance is unclear. The present studies aimed to determine: (i) the memory process(es) affected by systemic ALLO using a nonspatial object memory task; and (ii) whether ALLO affects object memory via an influence within the dorsal hippocampus. Male C57BL/6J mice received systemic ALLO either before or immediately after the sample session of a novel object recognition (NOR) task. Results demonstrated that systemic ALLO impaired the encoding and consolidation of object memory. A subsequent study revealed that bilateral microinfusion of ALLO into the CA1 region of dorsal hippocampus immediately following the NOR sample session also impaired object memory consolidation. In light of debate over the hippocampal-dependence of object recognition memory, we also tested systemic ALLO-treated mice on a contextual and cued fear-conditioning task. Systemic ALLO impaired the encoding of contextual memory when administered prior to the context pre-exposure session. Together, these results indicate that ALLO exhibits primary effects on memory encoding and consolidation, and extend previous findings by demonstrating a sensitivity of nonspatial memory to ALLO, likely by disrupting dorsal hippocampal function.

  2. Stress, memory, and the hippocampus.

    PubMed

    Wingenfeld, Katja; Wolf, Oliver T

    2014-01-01

    Stress hormones, i.e. cortisol in human and cortisone in rodents, influence a wide range of cognitive functions, including hippocampus-based declarative memory performance. Cortisol enhances memory consolidation, but impairs memory retrieval. In this context glucocorticoid receptor sensitivity and hippocampal integrity play an important role. This review integrates findings on the relationships between the hypothalamus-pituitary-adrenal (HPA) axis, one of the main coordinators of the stress response, hippocampus, and memory. Findings obtained in healthy participants will be compared with selected mental disorders, including major depressive disorder (MDD), posttraumatic stress disorder (PTSD), and borderline personality disorder (BPD). These disorders are characterized by alterations of the HPA axis and hippocampal dysfunctions. Interestingly, the acute effects of stress hormones on memory in psychiatric patients are different from those found in healthy humans. While cortisol administration has failed to affect memory retrieval in patients with MDD, patients with PTSD and BPD have been found to show enhanced rather than impaired memory retrieval after hydrocortisone. This indicates an altered sensitivity to stress hormones in these mental disorders.

  3. Effects of intra-hippocampal microinjection of vitamin B12 on the orofacial pain and memory impairments induced by scopolamine and orofacial pain in rats.

    PubMed

    Erfanparast, Amir; Tamaddonfard, Esmaeal; Nemati, Shaghayegh

    2017-03-01

    In the present study, we investigated the effects of microinjection of vitamin B12 into the hippocampus on the orofacial pain and memory impairments induced by scopolamine and orofacial pain. In ketamine-xylazine anesthetized rats, the right and left sides of the dorsal hippocampus (CA1) were implanted with two guide cannulas. Orofacial pain was induced by subcutaneous injection of formalin (1.5%, 50μl) into the right vibrissa pad, and the durations of face rubbing were recorded at 3-min blocks for 45min. Morris water maze (MWM) was used for evaluation of learning and memory. Finally, locomotor activity was assessed using an open-field test. Vitamin B12 attenuated both phases of formalin-induced orofacial pain. Prior administration of naloxone and naloxonazine, but not naltrindole and nor-binaltorphimine, prevented this effect. Vitamin B12 and physostigmine decreased latency time as well as traveled distance in Morris water maze. In addition, these chemicals improved scopolamine-induced memory impairment. The memory impairment induced by orofacial pain was improved by vitamin B12 and physostigmine used alone. Naloxone prevented, whereas physostigmine enhanced the memory improving effect of vitamin B12 in the pain-induced memory impairment. All the above-mentioned chemicals did not alter locomotor activity. The results of the present study showed that at the level of the dorsal hippocampus, vitamin B12 modulated orofacial pain through a mu-opioid receptor mechanism. In addition, vitamin B12 contributed to hippocampal cholinergic system in processing of memory. Moreover, cholinergic and opioid systems may be involved in improving effect of vitamin B12 on pain-induced memory impairment.

  4. Dorsal Hippocampal CREB Is Both Necessary and Sufficient for Spatial Memory

    ERIC Educational Resources Information Center

    Sekeres, Melanie J.; Neve, Rachael L.; Frankland, Paul W.; Josselyn, Sheena A.

    2010-01-01

    Although the transcription factor CREB has been widely implicated in memory, whether it is sufficient to produce spatial memory under conditions that do not normally support memory formation in mammals is unknown. We found that locally and acutely increasing CREB levels in the dorsal hippocampus using viral vectors is sufficient to induce robust…

  5. Dorsal spine osteoblastoma

    PubMed Central

    Bhargava, Pranshu; Singh, Rahul; Garg, Bharat B.

    2016-01-01

    Benign osteoblastoma is a rare primary neoplasm comprising less than 1% of primary bone tumors.[1] We report a case of a 20-year-old female patient presenting with progressive paraparesis over one year and back pain over the dorsal spine gradually increasing in severity over a year. Computerised tomomography (CT) of the spine revealed a well-defined 3.5 × 3.0 cm mass heterodense expansile bony lesion arising from the lamina of the D12 vertebra, having lytic and sclerotic component and causing compromise of the bony spinal canal. D12 laminectomy and total excision of the tumor was done. PMID:27057242

  6. Loss of hippocampal function impairs pattern separation on a mouse touch-screen operant paradigm.

    PubMed

    Josey, Megan; Brigman, Jonathan L

    2015-11-01

    The hippocampus is heavily involved in the learning and memory processes necessary to successfully encode environmental stimuli and representations over time. Impairment of hippocampal function is associated with numerous neuropsychiatric diseases and can lead to detriments in the quality of life. In order to take full advantage of preclinical models of these disorders, there is a need for the development of more refined measures of clinically relevant hippocampal behaviors. While arena-based navigation tasks have provided fundamental information regarding the role of the hippocampus in spatial memory, the development of automated operant variants have had mixed results. Recently, an automated touch-screen paradigm has been shown to be highly sensitive to hippocampal function in the rat and eliminated mediating strategies that arose in previous tasks. Here we show that mice with lesions encompassing the entire ventral portion of the dorsal hippocampus are impaired on pattern separation behavior using a delayed nonmatching-to-location (TUNL) adapted for mice. Lesioned mice readily acquired the task at control rates when separations were maximal and delay periods were short while decreasing separations significantly impaired lesion mice. However, in contrast to previously reported results in the rat, consistently increasing delays did not significantly impair performance in the lesion group. Presentation of a variable delay within a session significantly impaired performance in lesion mice across delay periods. The current results demonstrate the utility of a touch-screen paradigm for measuring hippocampal-dependent pattern separation in the mouse and establish the paradigm as an important platform for future studies in disease models.

  7. Low Doses of 17α-Estradiol and 17β-Estradiol Facilitate, Whereas Higher Doses of Estrone and 17α- and 17β-Estradiol Impair, Contextual Fear Conditioning in Adult Female Rats

    PubMed Central

    Barha, Cindy K; Dalton, Gemma L; Galea, Liisa AM

    2010-01-01

    Estrogens are known to exert significant structural and functional effects in the hippocampus of adult rodents. In particular, 17β-estradiol can improve, impair, or have no effect on hippocampus-dependent learning and memory depending on dose and time of administration. The effects of other forms of estrogen, such as estrone and 17α-estradiol, on hippocampus-dependent learning have not been as thoroughly investigated. Therefore, the purpose of this study was to investigate the effects of 17β-estradiol, estrone, and 17α-estradiol at three different doses on two different tasks: hippocampus-dependent contextual fear conditioning and hippocampus-independent cued fear conditioning. Adult ovariectomized female rats were injected with one of the estrogens at one of the three doses 30 mins before conditioning to assess the rapid effects of these estrogens on acquisition. Twenty-four hours later memory for the context was examined and 1 h later memory for the cue (tone) was assessed. Levels of synaptophysin were examined in the dorsal hippocampus of rats to identify a potential synaptic correlate of hormonal effects on contextual fear conditioning. Low 17β-estradiol and 17α-estradiol enhanced, whereas high 17β-estradiol and 17α-estradiol impaired, contextual fear conditioning. Only the middle dose of estrone severely impaired contextual fear conditioning. Estrogens did not alter performance in the hippocampus-independent cued task. Synaptophysin expression was increased by estrone (at a middle and high dose) and 17β-estradiol (at a middle dose) in the CA3 region of the hippocampus and was not correlated with cognition. The results of this study indicate that estradiol can positively or negatively influence hippocampus-dependent learning and memory, whereas estrone impairs hippocampus-dependent learning and memory in a dose-dependent manner. These results have important therapeutic implications, as estrone, a main component of a widely used hormone replacement

  8. Pointing in visual periphery: is DF's dorsal stream intact?

    PubMed

    Hesse, Constanze; Ball, Keira; Schenk, Thomas

    2014-01-01

    Observations of the visual form agnosic patient DF have been highly influential in establishing the hypothesis that separate processing streams deal with vision for perception (ventral stream) and vision for action (dorsal stream). In this context, DF's preserved ability to perform visually-guided actions has been contrasted with the selective impairment of visuomotor performance in optic ataxia patients suffering from damage to dorsal stream areas. However, the recent finding that DF shows a thinning of the grey matter in the dorsal stream regions of both hemispheres in combination with the observation that her right-handed movements are impaired when they are performed in visual periphery has opened up the possibility that patient DF may potentially also be suffering from optic ataxia. If lesions to the posterior parietal cortex (dorsal stream) are bilateral, pointing and reaching deficits should be observed in both visual hemifields and for both hands when targets are viewed in visual periphery. Here, we tested DF's visuomotor performance when pointing with her left and her right hand toward targets presented in the left and the right visual field at three different visual eccentricities. Our results indicate that DF shows large and consistent impairments in all conditions. These findings imply that DF's dorsal stream atrophies are functionally relevant and hence challenge the idea that patient DF's seemingly normal visuomotor behaviour can be attributed to her intact dorsal stream. Instead, DF seems to be a patient who suffers from combined ventral and dorsal stream damage meaning that a new account is needed to explain why she shows such remarkably normal visuomotor behaviour in a number of tasks and conditions.

  9. Dorsal column stimulator applications

    PubMed Central

    Yampolsky, Claudio; Hem, Santiago; Bendersky, Damián

    2012-01-01

    Background: Spinal cord stimulation (SCS) has been used to treat neuropathic pain since 1967. Following that, technological progress, among other advances, helped SCS become an effective tool to reduce pain. Methods: This article is a non-systematic review of the mechanism of action, indications, results, programming parameters, complications, and cost-effectiveness of SCS. Results: In spite of the existence of several studies that try to prove the mechanism of action of SCS, it still remains unknown. The mechanism of action of SCS would be based on the antidromic activation of the dorsal column fibers, which activate the inhibitory interneurons within the dorsal horn. At present, the indications of SCS are being revised constantly, while new applications are being proposed and researched worldwide. Failed back surgery syndrome (FBSS) is the most common indication for SCS, whereas, the complex regional pain syndrome (CRPS) is the second one. Also, this technique is useful in patients with refractory angina and critical limb ischemia, in whom surgical or endovascular treatment cannot be performed. Further indications may be phantom limb pain, chronic intractable pain located in the head, face, neck, or upper extremities, spinal lumbar stenosis in patients who are not surgical candidates, and others. Conclusion: Spinal cord stimulation is a useful tool for neuromodulation, if an accurate patient selection is carried out prior, which should include a trial period. Undoubtedly, this proper selection and a better knowledge of its underlying mechanisms of action, will allow this cutting edge technique to be more acceptable among pain physicians. PMID:23230533

  10. The hippocampus is required for visually cued contextual response selection, but not for visual discrimination of contexts

    PubMed Central

    Kim, Sehee; Lee, Jihyun; Lee, Inah

    2012-01-01

    The hippocampus is important for spatial navigation. Literature shows that allocentric visual contexts in the animal's background are critical for making conditional response selections during navigations. In a traditional maze task, however, it is difficult to identify exactly which subsets of visual contexts are critically used. In the current study, we tested in rats whether making conditional response selections required the hippocampus when using computer-generated visual contextual stimuli in the animal's background as in primate and human studies. We designed a new task, visual contextual response selection (VCRS) task, in which the rat ran along a linear track and encountered a touchscreen monitor at the end of the track. The rat was required to touch one of the adjacent rectangular box images depending on the visual contextual stimuli displayed in the two peripheral monitors positioned on both sides of the center touchscreen monitor. The rats with a GABA-A receptor agonist, muscimol (MUS), infused bilaterally in the dorsal hippocampi showed severe performance deficits in the VCRS task and the impairment was completely reversible with vehicle injections. The impairment in contextual response selection with hippocampal inactivations occurred regardless of whether the visual context was presented in the side monitors or in the center touchscreen monitor. However, when the same visual contextual stimuli were pitted against each other between the two side monitors and as the rats simply ran toward the visual context associated with reward on a T-shaped track, hippocampal inactivations with MUS showed minimal disruptions, if any, in performance. Our results suggest that the hippocampus is critically involved in conditional response selection using visual stimuli in the background, but it is not required for the perceptual discrimination of those stimuli. PMID:23060765

  11. Changes in acetylcholine content, release and muscarinic receptors in rat hippocampus under cold stress

    SciTech Connect

    Fatranska, M.; Budai, D.; Gulya, K; Kvetnansky, R.

    1989-01-01

    The aim was to study the mechanism of the previously established decrease in acetylcholine (ACh) concentration in the rat hippocampus under cold stress. Male rats were exposed for 14 days to cold (5/degree/C) or kept (controls) at room temperature (24/degree/C). Acetylcholine content, release and muscarinic receptor binding were investigated in the hippocampus. Cold exposure resulted in a decrease of ACh concentration in the dorsal hippocampus. Moreover, the potassium-evoked release of ACh from hippocampal slices was increased and an increase of maximal binding capacity of (/sup 3/H)(-) quinuclidinyl benzilate in the dorsal hippocampus of cold exposed animals was also observed. Thus the decrease of hippocampal ACh concentration under cold exposure is probably due to its increased release. On balance then, our results demonstrate that cold stress in the rat induces significant activation of the hippocampal cholinergic system.

  12. CPEB3 Deficiency Elevates TRPV1 Expression in Dorsal Root Ganglia Neurons to Potentiate Thermosensation

    PubMed Central

    Chen, Chih-Cheng; Huang, Yi-Shuian

    2016-01-01

    Cytoplasmic polyadenylation element binding protein 3 (CPEB3) is a sequence-specific RNA-binding protein that downregulates translation of multiple plasticity-related proteins (PRPs) at the glutamatergic synapses. Activity-induced synthesis of PRPs maintains long-lasting synaptic changes that are critical for memory consolidation and chronic pain manifestation. CPEB3-knockout (KO) mice show aberrant hippocampus-related plasticity and memory, so we investigated whether CPEB3 might have a role in nociception-associated plasticity. CPEB3 is widely expressed in the brain and peripheral afferent sensory neurons. CPEB3-KO mice with normal mechanosensation showed hypersensitivity to noxious heat. In the complete Freund's adjuvant (CFA)-induced inflammatory pain model, CPEB3-KO animals showed normal thermal hyperalgesia and transiently enhanced mechanical hyperalgesia. Translation of transient receptor potential vanilloid 1 (TRPV1) RNA was suppressed by CPEB3 in dorsal root ganglia (DRG), whereas CFA-induced inflammation reversed this inhibition. Moreover, CPEB3/TRPV1 double-KO mice behaved like TRPV1-KO mice, with severely impaired thermosensation and thermal hyperalgesia. An enhanced thermal response was recapitulated in non-inflamed but not inflamed conditional-KO mice, with cpeb3 gene ablated mostly but not completely, in small-diameter nociceptive DRG neurons. CPEB3-regulated translation of TRPV1 RNA may play a role in fine-tuning thermal sensitivity of nociceptors. PMID:26915043

  13. CREB overexpression in dorsal CA1 ameliorates long-term memory deficits in aged rats

    PubMed Central

    Yu, Xiao-Wen; Curlik, Daniel M; Oh, M Matthew; Yin, Jerry CP; Disterhoft, John F

    2017-01-01

    The molecular mechanisms underlying age-related cognitive deficits are not yet fully elucidated. In aged animals, a decrease in the intrinsic excitability of CA1 pyramidal neurons is believed to contribute to age-related cognitive impairments. Increasing activity of the transcription factor cAMP response element-binding protein (CREB) in young adult rodents facilitates cognition, and increases intrinsic excitability. However, it has yet to be tested if increasing CREB expression also ameliorates age-related behavioral and biophysical deficits. To test this hypothesis, we virally overexpressed CREB in CA1 of dorsal hippocampus. Rats received CREB or control virus, before undergoing water maze training. CREB overexpression in aged animals ameliorated the long-term memory deficits observed in control animals. Concurrently, cells overexpressing CREB in aged animals had reduced post-burst afterhyperpolarizations, indicative of increased intrinsic excitability. These results identify CREB modulation as a potential therapy to treat age-related cognitive decline. DOI: http://dx.doi.org/10.7554/eLife.19358.001 PMID:28051768

  14. The human lumbar dorsal rami.

    PubMed Central

    Bogduk, N; Wilson, A S; Tynan, W

    1982-01-01

    The L 1-4 dorsal rami tend to form three branches, medial, lateral, and intermediate, which are distributed, respectively, to multifidus, iliocostalis, and longissimus. The intertransversarii mediales are innervated by a branch of the dorsal ramus near the origin of the medial branch. The L 4 dorsal ramus regularly forms three branches while the L 1-3 levels the lateral and intermediate branches may, alternatively, arise from a short common stem. The L 5 dorsal ramus is much longer than the others and forms only a medial and an intermediate branch. Each lumbar medial branch innervates two adjacent zygapophysial joints and ramifies in multifidus, supplying only those fascicles which arise from the spinous process with the same segmental number as the nerve. The comparative anatomy of the lumbar dorsal rami is discussed and the applied anatomy with respect to 'rhizolysis', 'facet denervation' and diagnostic paraspinal electromyography is described. PMID:7076562

  15. Hippocampus and consciousness.

    PubMed

    Behrendt, Ralf-Peter

    2013-01-01

    An important assumption concerning the physiology of consciousness is that all varieties of conscious experience are closely related to each other and, hence, are subserved by the same neural mechanism. There are several considerations that lead us to implicate the hippocampus in the generation of conscious perception and, ultimately, of conscious experiences of all kinds. Firstly, conscious perception of external events is intricately linked with the formation of episodic (declarative) memories, a key function attributed to the hippocampus. Secondly, conscious experience is allocentric and contextualized. Consciousness creates or simulates an image of the world that appears to surround us and to be independent of our observation of it. What is characteristic of wakeful consciousness and dreaming alike is that objects or events are experienced as being embedded in an external, that is, allocentric, frame of space and time. The hippocampus has been implicated in the rapid formation and memorization of allocentric representations that embed objects or events in a world context. Thirdly, the hippocampus is ideally positioned to bind information processed in different sensory association cortices. It is argued that rapidly forming patterns of neuronal ensemble firing in the hippocampus, particularly in region CA3, which encode arbitrary associations between objects and their spatiotemporal and emotional context, that is, associations between information derived from different neocortical processing streams, define the informational content of consciousness. Evidence suggestive of an important contribution of the hippocampus to conscious observation, mental imagery, dreaming, conscious anticipation of outcomes, and hallucinations will be reviewed.

  16. Nicotine shifts the temporal activation of hippocampal protein kinase A and extracellular signal-regulated kinase 1/2 to enhance long-term, but not short-term, hippocampus-dependent memory.

    PubMed

    Gould, Thomas J; Wilkinson, Derek S; Yildirim, Emre; Poole, Rachel L F; Leach, Prescott T; Simmons, Steven J

    2014-03-01

    Acute nicotine enhances hippocampus-dependent learning through nicotine binding to β2-containing nicotinic acetylcholine receptors (nAChRs), but it is unclear if nicotine is targeting processes involved in short-term memory (STM) leading to a strong long-term memory (LTM) or directly targeting LTM. In addition, the molecular mechanisms involved in the effects of nicotine on learning are unknown. Previous research indicates that protein kinase A (PKA), extracellular signal-regulated kinase 1/2 (ERK1/2), and protein synthesis are crucial for LTM. Therefore, the present study examined the effects of nicotine on STM and LTM and the involvement of PKA, ERK1/2, and protein synthesis in the nicotine-induced enhancement of hippocampus-dependent contextual learning in C57BL/6J mice. The protein synthesis inhibitor anisomycin impaired contextual conditioning assessed at 4 h but not 2 h post-training, delineating time points for STM (2 h) and LTM (4 h and beyond). Nicotine enhanced contextual conditioning at 4, 8, and 24 h but not 2 h post-training, indicating nicotine specifically enhances LTM but not STM. Furthermore, nicotine did not rescue deficits in contextual conditioning produced by anisomycin, suggesting that the nicotine enhancement of contextual conditioning occurs through a protein synthesis-dependent mechanism. In addition, inhibition of dorsal hippocampal PKA activity blocked the effect of acute nicotine on learning, and nicotine shifted the timing of learning-related PKA and ERK1/2 activity in the dorsal and ventral hippocampus. Thus, the present results suggest that nicotine specifically enhances LTM through altering the timing of PKA and ERK1/2 signaling in the hippocampus, and suggests that the timing of PKA and ERK1/2 activity could contribute to the strength of memories.

  17. Specific impairment of "what-where-when" episodic-like memory in experimental models of temporal lobe epilepsy.

    PubMed

    Inostroza, Marion; Brotons-Mas, Jorge R; Laurent, François; Cid, Elena; de la Prida, Liset Menendez

    2013-11-06

    Episodic memory deficit is a common cognitive disorder in human temporal lobe epilepsy (TLE). However, no animal model of TLE has been shown to specifically replicate this cognitive dysfunction, which has limited its translational appeal. Here, using a task that tests for nonverbal correlates of episodic-like memory in rats, we show that kainate-treated TLE rats exhibit a selective impairment of the "what-where-when" memory while preserving other forms of hippocampal-dependent memories. Assisted by multisite silicon probes, we recorded from the dorsal hippocampus of behaving animals to control for seizure-related factors and to look for electrophysiological signatures of cognitive impairment. Analyses of hippocampal local field potentials showed that both the power of theta rhythm and its coordination across CA1 and the DG-measured as theta coherence and phase locking-were selectively disrupted. This disruption represented a basal condition of the chronic epileptic hippocampus that was linked to different features of memory impairment. Theta power was more correlated with the spatial than with the temporal component of the task, while measures of theta coordination correlated with the temporal component. We conclude that episodic-like memory, as tested in the what-where-when task, is specifically affected in experimental TLE and that the impairment of hippocampal theta activity might be central to this dysfunction.

  18. Investigating the functional integrity of the dorsal visual pathway in autism and dyslexia.

    PubMed

    Pellicano, Elizabeth; Gibson, Lisa Y

    2008-08-01

    Numerous reports of elevated global motion thresholds across a variety of neurodevelopmental disorders have prompted researchers to suggest that abnormalities in global motion perception are a result of a general deficiency in the dorsal visual pathway. To test this hypothesis, we assessed the integrity of the dorsal visual pathway at lower subcortical (sensitivity to flicker contrast) and higher cortical (sensitivity to global motion) levels in children with autism, children with dyslexia, and typically developing children, of similar age and ability. While children with autism demonstrated intact lower-level, but impaired higher-level dorsal-stream functioning, children with dyslexia displayed abnormalities at both lower and higher levels of the dorsal visual stream. These findings suggest that these disorders can be dissociated according to the origin of the impairment along the dorsal-stream pathway. Implications for general cross-syndrome accounts are discussed.

  19. Unilateral injection of Aβ25-35 in the hippocampus reduces the number of dendritic spines in hyperglycemic rats.

    PubMed

    Lazcano, Zayda; Solis, Oscar; Bringas, María Elena; Limón, Daniel; Diaz, Alfonso; Espinosa, Blanca; García-Peláez, Isabel; Flores, Gonzalo; Guevara, Jorge

    2014-07-22

    Alzheimer's disease (AD) is a neurodegenerative process exacerbated by several risk factors including impaired glucose metabolism in the brain that could cause molecular and neurochemical alterations in cognitive regions such as the hippocampus (Hp). Consequently, this process could cause neuronal morphological changes; however, the mechanism remains elusive. We induced chronic hyperglycemia after streptozotocin (STZ) administration. Then, we examined spatial learning and memory using the Morris water maze test and evaluated neuronal morphological changes using the Golgi-Cox stain procedure in hyperglycemic rats that received a Aβ25-35 unilateral injection into the Hp. Our results demonstrate that STZ combined with Aβ25-35 induced significant deficits in the spatial memory. In addition, we observed a significant reduction in the number of dendritic spines of pyramidal neurons in the dorsal Hp of rats with STZ plus Aβ25-35 . In conclusion, the reduced spine density of pyramidal neurons in the CA1 dorsal Hp could produce the spatial memory deficit observed in these animals. These results suggest that hyperglycemia can trigger Aβ-induced neurodegeneration and thus the appearance of AD symptoms would be accelerated. Synapse, 2014. © 2014 Wiley Periodicals, Inc.

  20. Topographic differences in adult neurogenesis in the mouse hippocampus: a stereology-based study using endogenous markers.

    PubMed

    Jinno, Shozo

    2011-05-01

    The hippocampus plays a critical role in various cognitive and affective functions. Increasing evidence shows that these functions are topographically distributed along the dorsoventral (septotemporal) and transverse axes of the hippocampus. For instance, dorsal hippocampus is involved in spatial memory and learning whereas ventral hippocampus is related to emotion. Here, we examined the topographic differences (dorsal vs. ventral; suprapyramidal vs. infrapyramidal) in adult neurogenesis in the mouse hippocampus using endogenous markers. The optical disector was applied to estimate the numerical densities (NDs) of labeled cells in the granule cell layer. The NDs of radial glia-like progenitors labeled by brain lipid binding protein were significantly lower in the infrapyramidal blade of the ventral DG than in other subdivisions. The NDs of doublecortin-expressing cells presumed neural progenitors and immature granule cells were significantly higher in the suprapyramidal blade of the dorsal DG than in the other subdivisions. The NDs of calretinin-expressing cells presumed young granule cells at the postmitotic stage were significantly higher in the suprapyramidal blade than in the infrapyramidal blade in the dorsal DG. No significant regional differences were detected in the NDs of dividing cells identified by proliferating cell nuclear antigen. Taken together, these findings suggest that a larger pool of immature granule cells in dorsal hippocampus might be responsible for spatial learning and memory, whereas a smaller pool of radial glia-like progenitors in ventral hippocampus might be associated with the susceptibility to affective disorders. Cell number estimation using a 300-μm-thick hypothetical slice indicates that regional differences in immature cells might contribute to the formation of topographic gradients in mature granule cells in the adult hippocampus. Our data also emphasizes the importance of considering such differences when evaluating changes in

  1. Dorsal Capsuloplasty for Dorsal Instability of the Distal Ulna

    PubMed Central

    Kouwenhoven, S.T.P.; de Jong, T.; Koch, A.R.

    2013-01-01

    Background Dorsal instability of the distal ulna can lead to chronic wrist pain and loss of function. Structural changes to the dorsal radioulnar ligaments (DRUL) of the triangular fibrocartilage complex (TFCC) and the dorsal capsule around the ulnar head with or without foveal detachment can lead to volar subluxation of the distal radius e.g., dorsal instability of the distal ulna. Purpose Is to evaluate the post-operative results of reinstituting distal radioulnar joint (DRUJ) stability through reefing of the dorsal capsule and dorsal radioulnar ligaments, with and without a foveal reattachment of the TFCC. Methods A total of 37 patients were included in this retrospective study. Diagnosis and treatment was based strictly on dry wrist arthroscopy. In 17 patients isolated reefing of the DRUL and their collateral tissue extension was performed. In 20 patients an additional foveal reinsertion was performed. Postoperative results were evaluated with the DASH questionnaire, VAS scores, grip strength and range of motion. These findings were extrapolated in the Mayo wrist score. The two subgroups were compared. Results Mayo wrist scores of the whole population had a mean of 73. There was no difference between the group that was treated with reefing of the DRUL only and the group that was treated with a combined foveal reinsertion. Conclusion This relatively simple 'dorsal reefing' procedure, with foveal reinsertion when indicated, is a reliable method to restore volar-dorsal DRUJ stability with a significant decrease in pain sensation, good DASH scores and restoration of functional grip strength and ROM. Type of Study/Level of Evidence Therapeutic, Level IV. PMID:24436811

  2. A Role for the Lateral Dorsal Tegmentum in Memory and Decision Neural Circuitry

    PubMed Central

    Redila, Van; Kinzel, Chantelle; Jo, Yong Sang; Puryear, Corey B.; Mizumori, Sheri J.Y.

    2017-01-01

    A role for the hippocampus in memory is clear, although the mechanism for its contribution remains a matter of debate. Converging evidence suggests that hippocampus evaluates the extent to which context-defining features of events occur as expected. The consequence of mismatches, or prediction error, signals from hippocampus is discussed in terms of its impact on neural circuitry that evaluates the significance of prediction errors: Ventral tegmental area (VTA) dopamine cells burst fire to rewards or cues that predict rewards (Schultz et al., 1997). Although the lateral dorsal tegmentum (LDTg) importantly controls dopamine cell burst firing (Lodge & Grace, 2006) the behavioral significance of the LDTg control is not known. Therefore, we evaluated LDTg functional activity as rats performed a spatial memory task that generates task-dependent reward codes in VTA (Jo et al., 2013; Puryear et al., 2010) and another VTA afferent, the pedunculopontine nucleus (PPTg, Norton et al., 2011). Reversible inactivation of the LDTg significantly impaired choice accuracy. LDTg neurons coded primarily egocentric information in the form of movement velocity, turning behaviors, and behaviors leading up to expected reward locations. A subset of the velocity-tuned LDTg cells also showed high frequency bursts shortly before or after reward encounters, after which they showed tonic elevated firing during consumption of small, but not large, rewards. Cells that fired before reward encounters showed stronger correlations with velocity as rats moved toward, rather than away from, rewarded sites. LDTg neural activity was more strongly regulated by egocentric behaviors than that observed for PPTg or VTA cells that were recorded by Puryear et al. and Norton et al. While PPTg activity was uniquely sensitive to ongoing sensory input, all three regions encoded reward magnitude (although in different ways), reward expectation, and reward encounters. Only VTA encoded reward prediction errors. LDTg

  3. Choline acetyltransferase in the hippocampus is associated with learning strategy preference in adult male rats.

    PubMed

    Hawley, Wayne R; Witty, Christine F; Daniel, Jill M; Dohanich, Gary P

    2015-08-01

    One principle of the multiple memory systems hypothesis posits that the hippocampus-based and striatum-based memory systems compete for control over learning. Consistent with this notion, previous research indicates that the cholinergic system of the hippocampus plays a role in modulating the preference for a hippocampus-based place learning strategy over a striatum-based stimulus--response learning strategy. Interestingly, in the hippocampus, greater activity and higher protein levels of choline acetyltransferase (ChAT), the enzyme that synthesizes acetylcholine, are associated with better performance on hippocampus-based learning and memory tasks. With this in mind, the primary aim of the current study was to determine if higher levels of ChAT and the high-affinity choline uptake transporter (CHT) in the hippocampus were associated with a preference for a hippocampus-based place learning strategy on a task that also could be solved by relying on a striatum-based stimulus--response learning strategy. Results confirmed that levels of ChAT in the dorsal region of the hippocampus were associated with a preference for a place learning strategy on a water maze task that could also be solved by adopting a stimulus-response learning strategy. Consistent with previous studies, the current results support the hypothesis that the cholinergic system of the hippocampus plays a role in balancing competition between memory systems that modulate learning strategy preference.

  4. Impaired novelty acquisition and synaptic plasticity in congenital hyperammonemia caused by hepatic glutamine synthetase deficiency

    PubMed Central

    Chepkova, Aisa N.; Sergeeva, Olga A.; Görg, Boris; Haas, Helmut L.; Klöcker, Nikolaj; Häussinger, Dieter

    2017-01-01

    Genetic defects in ammonia metabolism can produce irreversible damage of the developing CNS causing an impairment of cognitive and motor functions. We investigated alterations in behavior, synaptic plasticity and gene expression in the hippocampus and dorsal striatum of transgenic mice with systemic hyperammonemia resulting from conditional knockout of hepatic glutamine synthetase (LGS-ko). These mice showed reduced exploratory activity and delayed habituation to a novel environment. Field potential recordings from LGS-ko brain slices revealed significantly reduced magnitude of electrically-induced long-term potentiation (LTP) in both CA3-CA1 hippocampal and corticostriatal synaptic transmission. Corticostriatal but not hippocampal slices from LGS-ko brains demonstrated also significant alterations in long-lasting effects evoked by pharmacological activation of glutamate receptors. Real-time RT-PCR revealed distinct patterns of dysregulated gene expression in the hippocampus and striatum of LGS-ko mice: LGS-ko hippocampus showed significantly modified expression of mRNAs for mGluR1, GluN2B subunit of NMDAR, and A1 adenosine receptors while altered expression of mRNAs for D1 dopamine receptors, the M1 cholinoreceptor and the acetylcholine-synthetizing enzyme choline-acetyltransferase was observed in LGS-ko striatum. Thus, inborn systemic hyperammonemia resulted in significant deficits in novelty acquisition and disturbed synaptic plasticity in corticostriatal and hippocampal pathways involved in learning and goal-directed behavior. PMID:28067279

  5. Unsolved mysteries: the hippocampus.

    PubMed

    Isaacson, Robert L

    2002-06-01

    The continuing explosion of scientific interest in the hippocampus began in the 1950s, initiated in large part by the recognition of the importance of the observations of hippocampectomized monkeys made by Klüver and Bucy and the remarkable memory loss of patient H. M. following temporal lobe surgery. Subsequent to these studies, research and theories about the hippocampus grew exponentially in number and diversity. As yet, no theory of hippocampal function explains all of the phenomena discovered in the clinic or laboratory. In this article, experimental results that have been forgotten or ignored in most theories are presented. Adequate theories of hippocampal function must account for known, reliable postsurgical behavioral observations and consider the conditions under which anomalies are noted. Comprehensive theories will require new approaches in which the interactions of the hippocampus with the central nervous system are understood.

  6. Hippocampus and Medial Prefrontal Cortex Contributions to Trace and Contextual Fear Memory Expression over Time

    ERIC Educational Resources Information Center

    Beeman, Christopher L.; Bauer, Philip S.; Pierson, Jamie L.; Quinn, Jennifer J.

    2013-01-01

    Previous work has shown that damage to the dorsal hippocampus (DH) occurring at recent, but not remote, timepoints following acquisition produces a deficit in trace conditioned fear memory expression. The opposite pattern has been observed with lesions to the medial prefrontal cortex (mPFC). The present studies address: (1) whether these lesion…

  7. Serotonin Receptors in Hippocampus

    PubMed Central

    Berumen, Laura Cristina; Rodríguez, Angelina; Miledi, Ricardo; García-Alcocer, Guadalupe

    2012-01-01

    Serotonin is an ancient molecular signal and a recognized neurotransmitter brainwide distributed with particular presence in hippocampus. Almost all serotonin receptor subtypes are expressed in hippocampus, which implicates an intricate modulating system, considering that they can be localized as autosynaptic, presynaptic, and postsynaptic receptors, even colocalized within the same cell and being target of homo- and heterodimerization. Neurons and glia, including immune cells, integrate a functional network that uses several serotonin receptors to regulate their roles in this particular part of the limbic system. PMID:22629209

  8. The rodent hippocampus is essential for nonspatial object memory.

    PubMed

    Cohen, Sarah J; Munchow, Alcira H; Rios, Lisa M; Zhang, Gongliang; Asgeirsdóttir, Herborg N; Stackman, Robert W

    2013-09-09

    Elucidating the role of the rodent hippocampus in object recognition memory is critical for establishing the appropriateness of rodents as models of human memory and for their use in the development of memory disorder treatments. In mammals, spatial memory and nonspatial memory depend upon the hippocampus and associated medial temporal lobe (MTL) structures. Although well established in humans, the role of the rodent hippocampus in object memory remains highly debated due to conflicting findings across temporary and permanent hippocampal lesion studies and evidence that the perirhinal cortex may support object memory. In the current studies, we used intrahippocampal muscimol microinfusions to transiently inactivate the male C57BL/6J mouse hippocampus at distinct stages during the novel object recognition (NOR) task: during object memory encoding and consolidation, just consolidation, and/or retrieval. We also assessed the effect of temporary hippocampal inactivation when objects were presented in different contexts, thus eliminating the spatial or contextual components of the task. Lastly, we assessed extracellular dorsal hippocampal glutamate efflux and firing properties of hippocampal neurons while mice performed the NOR task. Our results reveal a clear and compelling role of the rodent hippocampus in nonspatial object memory.

  9. Neocortical activation of the hippocampus during sleep in infant rats.

    PubMed

    Mohns, Ethan J; Blumberg, Mark S

    2010-03-03

    We recently reported that the majority of hippocampal neurons in newborn rats increase their activity in association with myoclonic twitches, which are indicative of active sleep. Because spindle bursts in the developing somatosensory neocortex occur in response to sensory feedback from myoclonic twitching, we hypothesized that the state-dependent activity of the newborn hippocampus arises from sensory feedback that sequentially activates the neocortex and then hippocampus, constituting an early form of neocortical-hippocampal communication. Here, in unanesthetized 5- to 6-d-old rats, we test this hypothesis by recording simultaneously from forelimb and barrel regions of somatosensory neocortex and dorsal hippocampus during periods of spontaneous sleep and wakefulness and in response to peripheral stimulation. Myoclonic twitches were consistently followed by neocortical spindle bursts, which were in turn consistently followed by bursts of hippocampal unit activity; moreover, spindle burst power was positively correlated with hippocampal unit activity. In addition, exogenous stimulation consistently evoked this neocortical-to-hippocampal sequence of activation. Finally, parahippocampal lesions that disrupted functional connections between the neocortex and hippocampus effectively disrupted the transmission of both spontaneous and evoked neocortical activity to the hippocampus. These findings suggest that sleep-related motor activity contributes to the development of neocortical and hippocampal circuits and provides a foundation on which coordinated activity between these two forebrain structures develops.

  10. Rats use hippocampus to recognize positions of objects located in an inaccessible space.

    PubMed

    Levcik, D; Nekovarova, T; Stuchlik, A; Klement, D

    2013-02-01

    Rat hippocampus plays a crucial role in many spatial tasks, including recognition of position of objects, which can be approached and explored. Whether hippocampus is also necessary for recognizing positions of objects located in an inaccessible part of the environment remains unclear. To address this question, we conditioned rats to press a lever when an object displayed on a distant computer screen was in a particular position ("reward position") and not to press the lever when the object was in other positions ("nonreward positions"). After the rats had reached an asymptotic performance, the role of the dorsal hippocampus was assessed by blocking its activity with muscimol. The rats without functional dorsal hippocampus did not discriminate the reward position from the nonreward positions. Then the same rats were trained to discriminate light and dark conditions. The hippocampal inactivation did not disrupt the ability to discriminate these two conditions. It indicated that the inactivation itself had no major effect on the operant behavior and its control by visual stimuli. We conclude that rats use dorsal hippocampus for recognizing positions of objects located in an inaccessible part of the environment.

  11. High-Frequency Stimulation-Induced Synaptic Potentiation in Dorsal and Ventral CA1 Hippocampal Synapses: The Involvement of NMDA Receptors, mGluR5, and (L-Type) Voltage-Gated Calcium Channels

    ERIC Educational Resources Information Center

    Papatheodoropoulos, Costas; Kouvaros, Stylianos

    2016-01-01

    The ability of the ventral hippocampus (VH) for long-lasting long-term potentiation (LTP) and the mechanisms underlying its lower ability for shortlasting LTP compared with the dorsal hippocampus (DH) are unknown. Using recordings of field excitatory postsynaptic potentials (EPSPs) from the CA1 field of adult rat hippocampal slices, we found that…

  12. Memory, scene construction, and the human hippocampus.

    PubMed

    Kim, Soyun; Dede, Adam J O; Hopkins, Ramona O; Squire, Larry R

    2015-04-14

    We evaluated two different perspectives about the function of the human hippocampus--one that emphasizes the importance of memory and another that emphasizes the importance of spatial processing and scene construction. We gave tests of boundary extension, scene construction, and memory to patients with lesions limited to the hippocampus or large lesions of the medial temporal lobe. The patients were intact on all of the spatial tasks and impaired on all of the memory tasks. We discuss earlier studies that associated performance on these spatial tasks to hippocampal function. Our results demonstrate the importance of medial temporal lobe structures for memory and raise doubts about the idea that these structures have a prominent role in spatial cognition.

  13. Does the hippocampus keep track of time?

    PubMed

    Palombo, D J; Keane, M M; Verfaellie, M

    2016-03-01

    In the present study, we examined the role of the medial temporal lobe (MTL) in prospective time estimation at short and long timescales using a novel behavioral paradigm adapted from rodent work. Amnesic patients with MTL damage and healthy control participants estimated the duration of nature-based video clips that were either short (≤ 90 s) or long (more than 4 min). Consistent with previous work in rodents, we found that amnesic patients were impaired at making estimations for long, but not for short durations. Critically, these effects were observed in patients who had lesions circumscribed to the hippocampus, suggesting that the pattern observed was not attributable to the involvement of extra-hippocampal structures. That the MTL, and more specifically the hippocampus, is critical for prospective temporal estimation only at long intervals suggests that multiple neurobiological mechanisms support prospective time estimation.

  14. NEUROINFLAMMATION IN THE NORMAL AGING HIPPOCAMPUS

    PubMed Central

    BARRIENTOS, R. M.; KITT, M. M.; WATKINS, L. R.; MAIER, S. F.

    2015-01-01

    A consequence of normal aging is a greater susceptibility to memory impairments following an immune challenge such as infection, surgery, or traumatic brain injury. The neuroinflammatory response, produced by these challenges results in increased and prolonged production of pro-inflammatory cytokines in the otherwise healthy aged brain. Here we discuss the mechanisms by which long-lasting elevations in pro-inflammatory cytokines in the hippocampus produce memory impairments. Sensitized microglia are a primary source of this exaggerated neuroinflammatory response and appear to be a hallmark of the normal aging brain. We review the current understanding of the causes and effects of normal aging-induced microglial sensitization, including dysregulations of the neuroendocrine system, potentiation of neuroinflammatory responses following an immune challenge, and the impairment of memories. We end with a discussion of therapeutic approaches to prevent these deleterious effects. PMID:25772789

  15. Music exposure improves spatial cognition by enhancing the BDNF level of dorsal hippocampal subregions in the developing rats.

    PubMed

    Xing, Yingshou; Chen, Wenxi; Wang, Yanran; Jing, Wei; Gao, Shan; Guo, Daqing; Xia, Yang; Yao, Dezhong

    2016-03-01

    Previous research has shown that dorsal hippocampus plays an important role in spatial memory process. Music exposure can enhance brain-derived neurotrophic factor (BDNF) expression level in dorsal hippocampus (DH) and thus enhance spatial cognition ability. But whether music experience may affect different subregions of DH in the same degree remains unclear. Here, we studied the effects of exposure to Mozart K.448 on learning behavior in developing rats using the classical Morris water maze task. The results showed that early music exposure could enhance significantly learning performance of the rats in the water maze test. Meanwhile, the BDNF/TrkB level of dorsal hippocampus CA3 (dCA3) and dentate gyrus (dDG) was significantly enhanced in rats exposed to Mozart music as compared to those without music exposure. In contrast, the BDNF/TrkB level of dorsal hippocampus CA1 (dCA1) was not affected. The results suggest that the spatial memory improvement by music exposure in rats may be associated with the enhanced BDNF/TrkB level of dCA3 and dDG.

  16. Weak and nondiscriminative responses to conspecifics in the rat hippocampus.

    PubMed

    von Heimendahl, Moritz; Rao, Rajnish P; Brecht, Michael

    2012-02-08

    Little is known about how hippocampal neurons in rodents respond to and represent conspecifics. To address this question, we let rats interact while quantifying hippocampal neuronal activation patterns with extracellular recordings and immediate-early gene (c-Fos) expression. A total of 319 single putative pyramidal neurons was recorded in dorsal hippocampus. In sessions with multiple stimulus rats, no cell responded differentially to individual rats (N = 267 cells). We did find, however, that the presence of other rats induced a significant enhancement or suppression of firing in a fraction of neurons (n = 22 of 319; 7%). As expected, a large fraction of neurons (n = 170; 53%) had place fields. There was no evidence for place-independent responses to rats. Rather, the modulations were linked to the spatial responses. While neurons did not discriminate between individual rats, they did discriminate between rats and inanimate objects. Surprisingly, neuronal responses were more strongly modulated by objects than by rats, even though subjects spent more time near their conspecifics. Consistent with the low fraction of rat-modulated cells, social encounters did not induce c-Fos expression in the hippocampus, while there was a social interaction-specific expression in the basolateral amygdala. In both interacting and non-interacting rats, the fraction of c-Fos-expressing cells in the hippocampus was very low. Our investigation of social coding in the rat hippocampus, along with other recent work, showed that social responses were rare and lacked individual specificity, altogether speaking against a role of rodent dorsal hippocampus in social memory.

  17. Hippocampus, delay discounting, and vicarious trial-and-error.

    PubMed

    Bett, David; Murdoch, Lauren H; Wood, Emma R; Dudchenko, Paul A

    2015-05-01

    In decision-making, an immediate reward is usually preferred to a delayed reward, even if the latter is larger. We tested whether the hippocampus is necessary for this form of temporal discounting, and for vicarious trial-and-error at the decision point. Rats were trained on a recently developed, adjustable delay-discounting task (Papale et al. (2012) Cogn Affect Behav Neurosci 12:513-526), which featured a choice between a small, nearly immediate reward, and a larger, delayed reward. Rats then received either hippocampus or sham lesions. Animals with hippocampus lesions adjusted the delay for the larger reward to a level similar to that of sham-lesioned animals, suggesting a similar valuation capacity. However, the hippocampus lesion group spent significantly longer investigating the small and large rewards in the first part of the sessions, and were less sensitive to changes in the amount of reward in the large reward maze arm. Both sham- and hippocampus-lesioned rats showed a greater amount of vicarious trial-and-error on trials in which the delay was adjusted. In a nonadjusting version of the delay discounting task, animals with hippocampus lesions showed more variability in their preference for a larger reward that was delayed by 10 s compared with sham-lesioned animals. To verify the lesion behaviorally, rat were subsequently trained on a water maze task, and rats with hippocampus lesions were significantly impaired compared with sham-lesioned animals. The findings on the delay discounting tasks suggest that damage to the hippocampus may impair the detection of reward magnitude.

  18. Learning-facilitated synaptic plasticity occurs in the intermediate hippocampus in association with spatial learning

    PubMed Central

    Kenney, Jana; Manahan-Vaughan, Denise

    2013-01-01

    The dorsoventral axis of the hippocampus is differentiated into dorsal, intermediate, and ventral parts. Whereas the dorsal part is believed to specialize in processing spatial information, the ventral may be equipped to process non-spatial information. The precise role of the intermediate hippocampus is unclear, although recent data suggests it is functionally distinct, at least from the dorsal hippocampus. Learning-facilitated synaptic plasticity describes the ability of hippocampal synapses to respond with robust synaptic plasticity (>24 h) when a spatial learning event is coupled with afferent stimulation that would normally not lead to a lasting plasticity response: in the dorsal hippocampus novel space facilitates robust expression of long-term potentiation (LTP), whereas novel spatial content facilitates long-term depression (LTD). We explored whether the intermediate hippocampus engages in this kind of synaptic plasticity in response to novel spatial experience. In freely moving rats, high-frequency stimulation at 200 Hz (3 bursts of 15 stimuli) elicited synaptic potentiation that lasted for at least 4 h. Coupling of this stimulation with the exploration of a novel holeboard resulted in LTP that lasted for over 24 h. Low frequency afferent stimulation (1 Hz, 900 pulses) resulted in short-term depression (STD) that was significantly enhanced and prolonged by exposure to a novel large orientational (landmark) cues, however LTD was not enabled. Exposure to a holeboard that included novel objects in the holeboard holes elicited a transient enhancement of STD of the population spike (PS) but not field EPSP, and also failed to facilitate the expression of LTD. Our data suggest that the intermediate dentate gyrus engages in processing of spatial information, but is functionally distinct to the dorsal dentate gyrus. This may in turn reflect their assumed different roles in synaptic information processing and memory formation. PMID:24194716

  19. Post-Training Unilateral Amygdala Lesions Selectively Impair Contextual Fear Memories

    ERIC Educational Resources Information Center

    Flavell, Charlotte R.; Lee, Jonathan L. C.

    2012-01-01

    The basolateral amygdala (BLA) and the dorsal hippocampus (dHPC) are both structures with key roles in contextual fear conditioning. During fear conditioning, it is postulated that contextual representations of the environment are formed in the hippocampus, which are then associated with foot shock in the amygdala. However, it is not known to what…

  20. Stress Effects on the Hippocampus: A Critical Review

    ERIC Educational Resources Information Center

    Kim, Eun Joo; Pellman, Blake; Kim, Jeansok J.

    2015-01-01

    Uncontrollable stress has been recognized to influence the hippocampus at various levels of analysis. Behaviorally, human and animal studies have found that stress generally impairs various hippocampal-dependent memory tasks. Neurally, animal studies have revealed that stress alters ensuing synaptic plasticity and firing properties of hippocampal…

  1. Preliminary study of the regenerative processes of the dorsal cortex of the telencephalon of Lacerta viridis.

    PubMed

    Minelli, G; del Grande, P; Mambelli, M C

    1977-01-01

    The authors removed from Lacerta viridis specimens part of the dorsal hippocampus of one telencephalic hemisphere. The animals were sacrificed 110 and 260 days after the operation; 24 hours before the operation on the encephalon, each was dosed with 6--3H thymidine. An examination of the historadiographic slides showed a clear remedial process in the operated area which, 260 days after has renewed in thickness but was still minus its characteristic cellular layer. The area of the telencephalon affected by the remedial process was examined by the authors and they have put forward the hypothesis that in relation to the type of operation performed, said area is localized prevalently in the dorsal hippocampus of the caudal half of the telencephalic hemispherg. The authors have also shown that the remedial procress, though attenuated is still in progress. 260 days after the operation.

  2. The dorsal prefrontal and dorsal anterior cingulate cortices exert complementary network signatures during encoding and retrieval in associative memory.

    PubMed

    Woodcock, Eric A; White, Richard; Diwadkar, Vaibhav A

    2015-09-01

    Cognitive control includes processes that facilitate execution of effortful cognitive tasks, including associative memory. Regions implicated in cognitive control during associative memory include the dorsal prefrontal (dPFC) and dorsal anterior cingulate cortex (dACC). Here we investigated the relative degrees of network-related interactions originating in the dPFC and dACC during oscillating phases of associative memory: encoding and cued retrieval. Volunteers completed an established object-location associative memory paradigm during fMRI. Psychophysiological interactions modeled modulatory network interactions from the dPFC and dACC during memory encoding and retrieval. Results were evaluated in second level analyses of variance with seed region and memory process as factors. Each seed exerted differentiable modulatory effects during encoding and retrieval. The dACC exhibited greater modulation (than the dPFC) on the fusiform and parahippocampal gyrus during encoding, while the dPFC exhibited greater modulation (than the dACC) on the fusiform, hippocampus, dPFC and basal ganglia. During retrieval, the dPFC exhibited greater modulation (than the dACC) on the parahippocampal gyrus, hippocampus, superior parietal lobule, and dPFC. The most notable finding was a seed by process interaction indicating that the dACC and the dPFC exerted complementary modulatory control on the hippocampus during each of the associative memory processes. These results provide evidence for differentiable, yet complementary, control-related modulation by the dACC and dPFC, while establishing the primacy of dPFC in exerting network control during both associative memory phases. Our approach and findings are relevant for understanding basic processes in human memory and psychiatric disorders that impact associative memory-related networks.

  3. Histamine in the basolateral amygdala promotes inhibitory avoidance learning independently of hippocampus

    PubMed Central

    Benetti, Fernando; Furini, Cristiane Regina Guerino; de Carvalho Myskiw, Jociane; Provensi, Gustavo; Passani, Maria Beatrice; Baldi, Elisabetta; Bucherelli, Corrado; Munari, Leonardo; Izquierdo, Ivan; Blandina, Patrizio

    2015-01-01

    Recent discoveries demonstrated that recruitment of alternative brain circuits permits compensation of memory impairments following damage to brain regions specialized in integrating and/or storing specific memories, including both dorsal hippocampus and basolateral amygdala (BLA). Here, we first report that the integrity of the brain histaminergic system is necessary for long-term, but not for short-term memory of step-down inhibitory avoidance (IA). Second, we found that phosphorylation of cyclic adenosine monophosphate (cAMP) responsive-element-binding protein, a crucial mediator in long-term memory formation, correlated anatomically and temporally with histamine-induced memory retrieval, showing the active involvement of histamine function in CA1 and BLA in different phases of memory consolidation. Third, we found that exogenous application of histamine in either hippocampal CA1 or BLA of brain histamine-depleted rats, hence amnesic, restored long-term memory; however, the time frame of memory rescue was different for the two brain structures, short lived (immediately posttraining) for BLA, long lasting (up to 6 h) for the CA1. Moreover, long-term memory was formed immediately after training restoring of histamine transmission only in the BLA. These findings reveal the essential role of histaminergic neurotransmission to provide the brain with the plasticity necessary to ensure memorization of emotionally salient events, through recruitment of alternative circuits. Hence, our findings indicate that the histaminergic system comprises parallel, coordinated pathways that provide compensatory plasticity when one brain structure is compromised. PMID:25918368

  4. Histamine in the basolateral amygdala promotes inhibitory avoidance learning independently of hippocampus.

    PubMed

    Benetti, Fernando; Furini, Cristiane Regina Guerino; de Carvalho Myskiw, Jociane; Provensi, Gustavo; Passani, Maria Beatrice; Baldi, Elisabetta; Bucherelli, Corrado; Munari, Leonardo; Izquierdo, Ivan; Blandina, Patrizio

    2015-05-12

    Recent discoveries demonstrated that recruitment of alternative brain circuits permits compensation of memory impairments following damage to brain regions specialized in integrating and/or storing specific memories, including both dorsal hippocampus and basolateral amygdala (BLA). Here, we first report that the integrity of the brain histaminergic system is necessary for long-term, but not for short-term memory of step-down inhibitory avoidance (IA). Second, we found that phosphorylation of cyclic adenosine monophosphate (cAMP) responsive-element-binding protein, a crucial mediator in long-term memory formation, correlated anatomically and temporally with histamine-induced memory retrieval, showing the active involvement of histamine function in CA1 and BLA in different phases of memory consolidation. Third, we found that exogenous application of histamine in either hippocampal CA1 or BLA of brain histamine-depleted rats, hence amnesic, restored long-term memory; however, the time frame of memory rescue was different for the two brain structures, short lived (immediately posttraining) for BLA, long lasting (up to 6 h) for the CA1. Moreover, long-term memory was formed immediately after training restoring of histamine transmission only in the BLA. These findings reveal the essential role of histaminergic neurotransmission to provide the brain with the plasticity necessary to ensure memorization of emotionally salient events, through recruitment of alternative circuits. Hence, our findings indicate that the histaminergic system comprises parallel, coordinated pathways that provide compensatory plasticity when one brain structure is compromised.

  5. Increased anterior cingulate cortex and hippocampus activation in Complex PTSD during encoding of negative words

    PubMed Central

    Dorrepaal, Ethy; Draijer, Nel; de Ruiter, Michiel B.; Elzinga, Bernet M.; Sjoerds, Zsuzsika; van Balkom, Anton J.; Smit, Johannes H.; Veltman, Dick J.

    2013-01-01

    Post-traumatic stress disorder (PTSD) is associated with impaired memory performance coupled with functional changes in brain areas involved in declarative memory and emotion regulation. It is not yet clear how symptom severity and comorbidity affect neurocognitive functioning in PTSD. We performed a functional magnetic resonance imaging (fMRI) study with an emotional declarative memory task in 28 Complex PTSD patients with comorbid depressive and personality disorders, and 21 healthy non-trauma-exposed controls. In Complex PTSD patients—compared to controls—encoding of later remembered negative words vs baseline was associated with increased blood oxygenation level dependent (BOLD) response in the left ventral anterior cingulate cortex (ACC) and dorsal ACC extending to the dorsomedial prefrontal cortex (dmPFC) together with a trend for increased left hippocampus activation. Patients tended to commit more False Alarms to negative words compared to controls, which was associated with enhanced left ventrolateral prefrontal and orbitofrontal cortex (vlPFC/OFC) responses. Severity of child abuse was positively correlated with left ventral ACC activity and severity of depression with (para) hippocampal and ventral ACC activity. Presented results demonstrate functional abnormalities in Complex PTSD in the frontolimbic brain circuit also implicated in fear conditioning models, but generally in the opposite direction, which may be explained by severity of the trauma and severity of comorbid depression in Complex PTSD. PMID:22156722

  6. Methamphetamine differentially affects BDNF and cell death factors in anatomically defined regions of the hippocampus

    PubMed Central

    Galinato, Melissa H.; Orio, Laura; Mandyam, Chitra D.

    2014-01-01

    Methamphetamine exposure reduces hippocampal long-term potentiation (LTP) and neurogenesis and these alterations partially contribute to hippocampal maladaptive plasticity. The potential mechanisms underlying methamphetamine-induced maladaptive plasticity were identified in the present study. Expression of brain-derived neurotrophic factor (BDNF; a regulator of LTP and neurogenesis), and its receptor tropomyosin-related kinase B (TrkB) were studied in the dorsal and ventral hippocampal tissue lysates in rats that intravenously self-administered methamphetamine in a limited access (1 h/day) or extended access (6 h/day) paradigm for 17 days post baseline sessions. Extended access methamphetamine enhanced expression of BDNF with significant effects observed in the dorsal and ventral hippocampus. Methamphetamine-induced enhancements in BDNF expression were not associated with TrkB receptor activation as indicated by phospho (p)-TrkB-706 levels. Conversely, methamphetamine produced hypophosphorylation of NMDA receptor subunit 2B (GluN2B) at Tyr-1472 in the ventral hippocampus, indicating reduced receptor activation. In addition, methamphetamine enhanced expression of anti-apoptotic protein Bcl-2 and reduced pro-apoptotic protein Bax levels in the ventral hippocampus, suggesting a mechanism for reducing cell death. Analysis of Akt, a pro-survival kinase that suppresses apoptotic pathways and pAkt at Ser-473 demonstrated that extended access methamphetamine reduces Akt expression in the ventral hippocampus. These data reveal that alterations in Bcl-2 and Bax levels by methamphetamine were not associated with enhanced Akt expression. Given that hippocampal function and neurogenesis vary in a subregion-specific fashion, where dorsal hippocampus regulates spatial processing and has higher levels of neurogenesis, whereas ventral hippocampus regulates anxiety-related behaviors, these data suggest that methamphetamine self-administration initiates distinct allostatic changes in

  7. Methamphetamine differentially affects BDNF and cell death factors in anatomically defined regions of the hippocampus.

    PubMed

    Galinato, M H; Orio, L; Mandyam, C D

    2015-02-12

    Methamphetamine exposure reduces hippocampal long-term potentiation (LTP) and neurogenesis and these alterations partially contribute to hippocampal maladaptive plasticity. The potential mechanisms underlying methamphetamine-induced maladaptive plasticity were identified in the present study. Expression of brain-derived neurotrophic factor (BDNF; a regulator of LTP and neurogenesis), and its receptor tropomyosin-related kinase B (TrkB) were studied in the dorsal and ventral hippocampal tissue lysates in rats that intravenously self-administered methamphetamine in a limited access (1h/day) or extended access (6h/day) paradigm for 17days post baseline sessions. Extended access methamphetamine enhanced expression of BDNF with significant effects observed in the dorsal and ventral hippocampus. Methamphetamine-induced enhancements in BDNF expression were not associated with TrkB receptor activation as indicated by phospho (p)-TrkB-706 levels. Conversely, methamphetamine produced hypophosphorylation of N-methyl-d-aspartate (NMDA) receptor subunit 2B (GluN2B) at Tyr-1472 in the ventral hippocampus, indicating reduced receptor activation. In addition, methamphetamine enhanced expression of anti-apoptotic protein Bcl-2 and reduced pro-apoptotic protein Bax levels in the ventral hippocampus, suggesting a mechanism for reducing cell death. Analysis of Akt, a pro-survival kinase that suppresses apoptotic pathways and pAkt at Ser-473 demonstrated that extended access methamphetamine reduces Akt expression in the ventral hippocampus. These data reveal that alterations in Bcl-2 and Bax levels by methamphetamine were not associated with enhanced Akt expression. Given that hippocampal function and neurogenesis vary in a subregion-specific fashion, where dorsal hippocampus regulates spatial processing and has higher levels of neurogenesis, whereas ventral hippocampus regulates anxiety-related behaviors, these data suggest that methamphetamine self-administration initiates distinct

  8. Dissociable effects of dorsal and ventral hippocampal DHA content on spatial learning and anxiety-like behavior.

    PubMed

    Jašarević, Eldin; Hecht, Patrick M; Fritsche, Kevin L; Beversdorf, David Q; Geary, David C

    2014-12-01

    Chronic deficiency of dietary docosahexaenoic acid (DHA) during critical developmental windows results in severe deficits in spatial learning, anxiety and hippocampal neuroplasticity that parallel a variety of neuropsychiatric disorders. However, little is known regarding the influence of long-term, multigenerational exposure to dietary DHA enrichment on these same traits. To characterize the potential benefits of multigenerational DHA enrichment, mice were fed a purified 10:1 omega-6/omega-3 diet supplemented with either 0.1% preformed DHA/kg feed weight or 1.0% preformed DHA/kg feed weight through three generations. General locomotor activity, spatial learning, and anxiety-like behavior were assessed in adult male offspring of the third generation. Following behavioral assessments, ventral and dorsal hippocampus was collected for DHA and arachidonic acid (AA) analysis. Animals consuming the 0.1% and 1.0% DHA diet did not differ from control animals for locomotor activity or on performance during acquisition learning, but made fewer errors and showed more stable across-day performance during reversal learning on the spatial task and showed less anxiety-like behavior. Consumption of the DHA-enriched diets increased DHA content in the ventral and dorsal hippocampus in a region-specific manner. DHA content in the dorsal hippocampus predicted performance on the reversal training task. DHA content in the ventral hippocampus was correlated with anxiety-like behavior, but AA content in the dorsal hippocampus was a stronger predictor of this behavior. These results suggest that long-term, multigenerational DHA administration improves performance on some aspects of complex spatial learning, decreases anxiety-like behavior, and that modulation of DHA content in sub-regions of the hippocampus predicts which behaviors are likely to be affected.

  9. Medial entorhinal cortex lesions only partially disrupt hippocampal place cells and hippocampus-dependent place memory

    PubMed Central

    Hales, Jena B; Schlesiger, Magdalene I; Leutgeb, Jill K; Squire, Larry R; Leutgeb, Stefan; Clark, Robert E

    2014-01-01

    SUMMARY Entorhinal cortex provides the primary cortical projections to the hippocampus, a brain structure critical for memory. However, it remains unclear how the precise firing patterns of medial entorhinal cortex (MEC) cells influence hippocampal physiology and hippocampus-dependent behavior. We found that complete bilateral lesions of MEC resulted in a lower proportion of active hippocampal cells. The remaining active cells had place fields, but with decreased spatial precision and decreased long-term spatial stability. In addition, MEC rats were as impaired at acquiring the watermaze as hippocampus rats, while rats with combined MEC and hippocampal lesions had an even greater deficit. However, MEC rats were not impaired on other hippocampus-dependent tasks, including those in which an object location or context was remembered. Thus, MEC is not necessary for all types of spatial coding, nor for all types of hippocampus-dependent memory, but is necessary for the normal acquisition of place memory. PMID:25437546

  10. Exercise Prevents Memory Impairment Induced by Arsenic Exposure in Mice: Implication of Hippocampal BDNF and CREB.

    PubMed

    Sun, Bao-Fei; Wang, Qing-Qing; Yu, Zi-Jiang; Yu, Yan; Xiao, Chao-Lun; Kang, Chao-Sheng; Ge, Guo; Linghu, Yan; Zhu, Jun-De; Li, Yu-Mei; Li, Qiang-Ming; Luo, Shi-Peng; Yang, Dang; Li, Lin; Zhang, Wen-Yan; Tian, Guang

    2015-01-01

    High concentrations of arsenic, which can be occasionally found in drinking water, have been recognized as a global health problem. Exposure to arsenic can disrupt spatial memory; however, the underlying mechanism remains unclear. In the present study, we tested whether exercise could interfere with the effect of arsenic exposure on the long-term memory (LTM) of object recognition in mice. Arsenic (0, 1, 3, and 10 mg/ kg, i.g.) was administered daily for 12 weeks. We found that arsenic at dosages of 1, 3, and 10 mg/kg decreased body weight and increased the arsenic content in the brain. The object recognition LTM (tested 24 h after training) was disrupted by 3 mg/ kg and 10 mg/ kg, but not 1 mg/ kg arsenic exposure. Swimming exercise also prevented LTM impairment induced by 3 mg/ kg, but not with 10 mg/ kg, of arsenic exposure. The expression of brain-derived neurotrophic factor (BDNF) and phosphorylated cAMP-response element binding protein (pCREB) in the CA1 and dentate gyrus areas (DG) of the dorsal hippocampus were decreased by 3 mg/ kg and 10 mg/ kg, but not by 1 mg/ kg, of arsenic exposure. The decrease in BDNF and pCREB in the CA1 and DG induced by 3 mg/ kg, but not 10 mg/ kg, of arsenic exposure were prevented by swimming exercise. Arsenic exposure did not affect the total CREB expression in the CA1 or DG. Taken together, these results indicated that swimming exercise prevented the impairment of object recognition LTM induced by arsenic exposure, which may be mediated by BDNF and CREB in the dorsal hippocampus.

  11. Exercise Prevents Memory Impairment Induced by Arsenic Exposure in Mice: Implication of Hippocampal BDNF and CREB

    PubMed Central

    Yu, Zi-Jiang; Yu, Yan; Xiao, Chao-Lun; Kang, Chao-Sheng; Ge, Guo; Linghu, Yan; Zhu, Jun-De; Li, Yu-Mei; Li, Qiang-Ming; Luo, Shi-Peng; Yang, Dang; Li, Lin; Zhang, Wen-Yan; Tian, Guang

    2015-01-01

    High concentrations of arsenic, which can be occasionally found in drinking water, have been recognized as a global health problem. Exposure to arsenic can disrupt spatial memory; however, the underlying mechanism remains unclear. In the present study, we tested whether exercise could interfere with the effect of arsenic exposure on the long-term memory (LTM) of object recognition in mice. Arsenic (0, 1, 3, and 10 mg/ kg, i.g.) was administered daily for 12 weeks. We found that arsenic at dosages of 1, 3, and 10 mg/kg decreased body weight and increased the arsenic content in the brain. The object recognition LTM (tested 24 h after training) was disrupted by 3 mg/ kg and 10 mg/ kg, but not 1 mg/ kg arsenic exposure. Swimming exercise also prevented LTM impairment induced by 3 mg/ kg, but not with 10 mg/ kg, of arsenic exposure. The expression of brain-derived neurotrophic factor (BDNF) and phosphorylated cAMP-response element binding protein (pCREB) in the CA1 and dentate gyrus areas (DG) of the dorsal hippocampus were decreased by 3 mg/ kg and 10 mg/ kg, but not by 1 mg/ kg, of arsenic exposure. The decrease in BDNF and pCREB in the CA1 and DG induced by 3 mg/ kg, but not 10 mg/ kg, of arsenic exposure were prevented by swimming exercise. Arsenic exposure did not affect the total CREB expression in the CA1 or DG. Taken together, these results indicated that swimming exercise prevented the impairment of object recognition LTM induced by arsenic exposure, which may be mediated by BDNF and CREB in the dorsal hippocampus. PMID:26368803

  12. The ventral hippocampus is the embryonic origin for adult neural stem cells in the dentate gyrus.

    PubMed

    Li, Guangnan; Fang, Li; Fernández, Gloria; Pleasure, Samuel J

    2013-05-22

    Adult neurogenesis represents a unique form of plasticity in the dentate gyrus requiring the presence of long-lived neural stem cells (LL-NSCs). However, the embryonic origin of these LL-NSCs remains unclear. The prevailing model assumes that the dentate neuroepithelium throughout the longitudinal axis of the hippocampus generates both the LL-NSCs and embryonically produced granule neurons. Here we show that the NSCs initially originate from the ventral hippocampus during late gestation and then relocate into the dorsal hippocampus. The descendants of these cells are the source for the LL-NSCs in the subgranular zone (SGZ). Furthermore, we show that the origin of these cells and their maintenance in the dentate are controlled by distinct sources of Sonic Hedgehog (Shh). The revelation of the complexity of both the embryonic origin of hippocampal LL-NSCs and the sources of Shh has important implications for the functions of LL-NSCs in the adult hippocampus.

  13. Role of dorsal hippocampal orexin-1 receptors in memory restoration induced by morphine sensitization phenomenon.

    PubMed

    Alijanpour, S; Tirgar, F; Zarrindast, M-R

    2016-01-15

    The present study was examined the blockade of CA1 orexin-1 receptors (OX1Rs) of the dorsal hippocampus in the induction or expression phase on morphine sensitization-induced memory restoration using the Morris water maze (MWM) apparatus. Results showed that pre-training administration of morphine (5mg/kg, s.c.) increases escape latency and traveled distance, while does not alter swimming speed. This supports the impairing effect of morphine on the spatial memory acquisition in male adult rats. Also, in the retrieval session (probe trial) this treatment decreased the time spent in the target quadrant. Moreover, morphine-induced sensitization (15 or 20mg/kg, s.c.; once daily for 3days and followed by 5days no drug treatment) restored the memory acquisition/retrieval deficit which had been induced by pre-training administration of morphine (5mg/kg, s.c.). Intra-CA1 microinjection of subthreshold doses of SB-334867 (OX1Rs antagonist; 10, 20 and 40nmol/rat), 5min before morphine (20mg/kg/day×3days, s.c.; induction phase for morphine sensitization) did not alter restoration of memory acquisition/retrieval produced by the morphine sensitization phenomenon. In contrast, microinjection of subthreshold doses of SB-334867 (10, 20 and 40nmol/rat) into the CA1 region in the training session, 5min prior to morphine (5mg/kg, s.c.; expression phase for morphine sensitization) blocked the spatial memory acquisition/retrieval in morphine-sensitized rats. In conclusion, these findings show that morphine sensitization reverses morphine-induced amnesia. Furthermore, the blockade of CA1 OX1Rs in the expression phase, but not in the induction phase, disrupts memory restoration induced by morphine sensitization.

  14. EPINEPHRINE AND GLUCOSE MODULATE TRAINING-RELATED CREB PHOSPHORYLATION IN OLD RATS: RELATIONSHIPS TO AGE-RELATED MEMORY IMPAIRMENTS

    PubMed Central

    Morris, Ken A.; Gold, Paul E.

    2012-01-01

    Epinephrine enhances memory in young adult rats, in part, by increasing blood glucose levels needed to modulate memory. In old rats, epinephrine is deficient at raising blood glucose levels and thus is only moderately effective at enhancing memory. In contrast, systemic glucose injections improve memory in old rats, with resulting memory performance equal to that of young rats. The diminished response of glucose to training in old rats may blunt downstream neurochemical and molecular mechanisms needed to upregulate memory processes. In the first experiment, young adult and old rats were trained on an inhibitory avoidance task with immediate post-training injections of aCSF or glucose into the dorsal hippocampus. Old rats had significant memory impairments compared to young rats 7 days after training. Intrahippocampal injections of glucose reversed age-related deficits, improving memory scores in old rats to values seen in young rats. A second experiment examined age-related changes in activation of the transcription factor CREB, which is widely implicated in memory formation and may act downstream of hormonal and metabolic signals. Activation was assessed in response to training with systemic injections of epinephrine and glucose at doses known to enhance memory. Young adult and old rats were trained on inhibitory avoidance with immediate post-training systemic injections of saline, epinephrine, or glucose. After training, old rats had significant impairments in CREB phosphorylation in area CA1 and the dentate gyrus region of the hippocampus, and in the basolateral and lateral amygdala. Epinephrine and glucose attenuated age-related deficits in CREB phosphorylation, but were more effective in the amygdala and hippocampus, respectively. Together, these results support the view that age-related changes in blood glucose responses to epinephrine contribute to memory impairments, which may be related to alterations in regional patterns of CREB phosphorylation. PMID

  15. Epinephrine and glucose modulate training-related CREB phosphorylation in old rats: relationships to age-related memory impairments.

    PubMed

    Morris, Ken A; Gold, Paul E

    2013-02-01

    Epinephrine enhances memory in young adult rats, in part, by increasing blood glucose levels needed to modulate memory. In old rats, epinephrine is deficient at raising blood glucose levels and thus is only moderately effective at enhancing memory. In contrast, systemic glucose injections improve memory in old rats, with resulting memory performance equal to that of young rats. The diminished response of glucose to training in old rats may blunt downstream neurochemical and molecular mechanisms needed to upregulate memory processes. In the first experiment, young adult and old rats were trained on an inhibitory avoidance task with immediate post-training injections of aCSF or glucose into the dorsal hippocampus. Old rats had significant memory impairments compared to young rats 7 days after training. Intrahippocampal injections of glucose reversed age-related deficits, improving memory scores in old rats to values seen in young rats. A second experiment examined age-related changes in activation of the transcription factor CREB, which is widely implicated in memory formation and may act downstream of hormonal and metabolic signals. Activation was assessed in response to training with systemic injections of epinephrine and glucose at doses known to enhance memory. Young adult and old rats were trained on inhibitory avoidance with immediate post-training systemic injections of saline, epinephrine, or glucose. After training, old rats had significant impairments in CREB phosphorylation in area CA1 and the dentate gyrus region of the hippocampus, and in the basolateral and lateral amygdala. Epinephrine and glucose attenuated age-related deficits in CREB phosphorylation, but were more effective in the amygdala and hippocampus, respectively. Together, these results support the view that age-related changes in blood glucose responses to epinephrine contribute to memory impairments, which may be related to alterations in regional patterns of CREB phosphorylation.

  16. Hippocampus is necessary for spatial discrimination using distal cue-configuration.

    PubMed

    Kim, Jangjin; Lee, Inah

    2011-06-01

    The role of the hippocampus in processing contextual cues has been well recognized. Contextual manipulation often involves transferring animals between different rooms. Because of vague definition of context in such a paradigm, however, it has been difficult to study the role of the hippocampus parametrically in contextual information processing. We designed a novel task in which a different context can be parametrically defined by the spatial configuration of distal cues. In this task, rats were trained to associate two different configurations of distal cue-sets (standard contexts) with different food-well locations at the end of a radial arm. Experiment 1 tested the role of the dorsal hippocampus in retrieving well-learned associations between standard contexts and rewarding food-well locations by comparing rats with neurotoxic lesions in the dorsal hippocampus with controls. We found that the hippocampal-lesioned rats were unable to retrieve the context-place paired associations learned before surgery. To further test the role of the hippocampus in generalizing altered context, in Experiment 2, rats were trained in a task in which modified versions of the standard contexts (ambiguous contexts) were presented, intermixed with the standard contexts. Rats were able to process the ambiguous contexts immediately by using their similarities to the standard contexts, whereas muscimol inactivation of the dorsal hippocampus in the same animals reversibly deprived such capability. The results suggest that rats can effectively associate discrete spatial locations with spatial configuration of distal cues. More important, rats can generalize or orthogonalize modified contextual environments using learned contextual representation of the environment.

  17. Regional Convection-Enhanced Delivery of Gadolinium-labeled Albumin in the Rat Hippocampus In Vivo

    PubMed Central

    Astary, Garrett W.; Kantorovich, Svetlana; Carney, Paul R.; Mareci, Thomas H.; Sarntinoranont, Malisa

    2010-01-01

    Convection-enhanced delivery (CED) has emerged as a promising method of targeted drug-delivery for treating central nervous system (CNS) disorders, but the influence of brain structure on infusate distribution is unclear. We have utilized this approach to study extracellular transport and distribution of a contrast agent in the hippocampus, a complex structure susceptible to CNS disorders. The magnetic resonance (MR) contrast agent diethylene triamene penta-acetic acid chelated gadolinium-labeled albumin (Gd-albumin), tagged with Evans blue dye, was directly infused into the dorsal and ventral hippocampus of seven male Sprague-Dawley rats. The final distribution profile of the contrast agent, a product of CED and limited diffusion, was observed in vivo using high-resolution T1-weighted MR imaging at 11.1 Tesla. Dense cell layers, such as the granule cell layer of the dentate gyrus and the pyramidal cell layer of CA1, appeared to be barriers to transport of the tracer. Three-dimensional distribution shape and volume (Vd) differences, between the dorsal and ventral hippocampus infusions, were determined from the MR images using a semi-automatic segmentation routine (Dorsal Vd = 23.4 ± 1.8 μl, Ventral Vd = 36.4 ± 5.1 μl). Finer structural detail of the hippocampus was obtained using a combination of histological analysis and fluorescence imaging. This study demonstrates that CED has the potential to target all regions of the hippocampus and that tracer distribution is influenced by infusion site, underlying structure and circuitry, and extent of backflow. Therefore, CED, combined with high-resolution MR imaging, may be a useful strategy for delivering therapeutics for the treatment of CNS disorders affecting the hippocampus. PMID:20067808

  18. [The administration of interleukin-1beta during early postnatal develop ment impairs FGF2, but not TIMP1, mRNA expression in brain structures of adult rats].

    PubMed

    Trofimov, A N; Zubareva, O E; Shvarts, A P; Ishchenko, A M; Klimenko, V M

    2014-09-01

    According to the Neurodevelopmental hypothesis, the long-lasting cognitive deficit in schizophrenia and other types of neuropathology may occur by injurious factors, such as hypoxia, traumas, infections that take place during pre- and postnatal development, at least at early stages. These pathological conditions are often associated with the high production of pro-inflammatory cytokine interleukin-1B (IL-1B) by the cells of immune and nervous systems. We investigated the expression of genes involved in the neuroplastic regulation (Fgf2 and Timp2) in medial prefrontal cortex and dorsal and ventral regions of hippocampus of adult rats that were treated with IL-1beta between P15 and P21. The learning impairment in IL-1beta-treated rats is accompanied by lower FGF-2 mRNA levels in medial prefrontal cortex and ventral (not dorsal) hippocampus, but TIMP-1 was not affected. No differences in TIMP-1 and FGF-2 mRNA expressions were observed in untrained IL-1beta-treated when compared to control rats.

  19. α4βδ GABAA receptors reduce dendritic spine density in CA1 hippocampus and impair relearning ability of adolescent female mice: Effects of a GABA agonist and a stress steroid.

    PubMed

    Afroz, Sonia; Shen, Hui; Smith, Sheryl S

    2017-04-07

    Synaptic pruning underlies the transition from an immature to an adult CNS through refinements of neuronal circuits. Our recent study indicates that pubertal synaptic pruning is triggered by the inhibition generated by extrasynaptic α4βδ GABAA receptors (GABARs) which are increased for 10 d on dendritic spines of CA1 pyramidal cells at the onset of puberty (PND 35-44) in the female mouse, suggesting α4βδ GABARs as a novel target for the regulation of adolescent synaptic pruning. In the present study we used a pharmacological approach to further examine the role of these receptors in altering spine density during puberty of female mice and the impact of these changes on spatial learning, assessed in adulthood. Two drugs were chronically administered during the pubertal period (PND 35-44): the GABA agonist gaboxadol (GBX, 0.1mg/kg, i.p.), to enhance current gated by α4βδ GABARs and the neurosteroid/stress steroid THP (3α-OH-5β-pregnan-20-one, 10mg/kg, i.p.) to decrease expression of α4βδ. Spine density was determined on PND 56 with Golgi staining. Spatial learning and relearning were assessed using the multiple object relocation task and an active place avoidance task on PND 56. Pubertal GBX decreased spine density post-pubertally by 70% (P<0.05), while decreasing α4βδ expression with THP increased spine density by twofold (P<0.05), in both cases, with greatest effects on the mushroom spines. Adult relearning ability was compromised in both hippocampus-dependent tasks after pubertal administration of either drug. These findings suggest that an optimal spine density produced by α4βδ GABARs is necessary for optimal cognition in adults.

  20. Dorsal hippocampal cannabinoid CB1 receptors mediate the interactive effects of nicotine and ethanol on passive avoidance learning in mice.

    PubMed

    Alijanpour, Sakineh; Rezayof, Ameneh; Zarrindast, Mohammad-Reza

    2013-03-01

    The present study evaluated the involvement of the dorsal hippocampal cannabinoid CB1 receptors in the combined effect of ethanol and nicotine on passive avoidance learning in adult male mice. The results indicated that pre-training administration of ethanol (1 g/kg, i.p.) impaired memory retrieval. Pre-test administration of ethanol (0.5 and 1 g/kg, i.p.) or nicotine (0.5 and 0.7 mg/kg, s.c.) significantly reversed ethanol-induced amnesia, suggesting a functional interaction between ethanol and nicotine. Pre-test microinjection of a selective CB1 receptor agonist, ACPA (3 and 5 ng/mouse), plus an ineffective dose of ethanol (0.25 g/kg) or nicotine (0.3 mg/kg) improved memory retrieval, while ACPA by itself could not reverse ethanol-induced amnesia. Pre-test intra-CA1 microinjection of a selective CB1 receptor antagonist, AM251 (0.5-2 ng/mouse), did not lead to a significant change in ethanol-induced amnesia. However, pre-test intra-CA1 microinjection of AM251 prevented the ethanol (1 g/kg) or nicotine (0.7 mg/kg) response on ethanol-induced amnesia. In order to support the involvement of the dorsal hippocampal CB1 receptors in nicotine response, the scheduled mixed treatments of AM251 (0.1-1 ng/mouse), ACPA (5 ng/mouse) and nicotine (0.3 mg/kg) were used. The results indicated that AM251 reversed the response of ACPA to the interactive effects of nicotine and ethanol in passive avoidance learning. Furthermore, pre-test intra-CA1 microinjection of the same doses of ACPA or AM251 had no effect on memory retrieval. These findings show that the cannabinoid CB1 receptors of dorsal hippocampus are important in the combined effect of ethanol and nicotine on passive avoidance learning.

  1. Galanin inhibits acetylcholine release in the ventral hippocampus of the rat: histochemical, autoradiographic, in vivo, and in vitro studies

    SciTech Connect

    Fisone, G.; Wu, C.F.; Consolo, S.; Nordstroem, O.; Brynne, N.; Bartfai, T.; Melander, T.; Hoekfelt, T.

    1987-10-01

    A high density of galanin binding sites was found by using /sup 125/I-labeled galanin, iodinated by chloramine-T, followed by autoradiography in the ventral, but not in the dorsal, hippocampus of the rat. Lesions of the fimbria and of the septum caused disappearance of a major population of these binding sites, suggesting that a large proportion of them is localized on cholinergic nerve terminals of septal afferents. As a functional correlate to these putative galanin receptor sites, it was shown, both in vivo and in vitro, that galanin, in a concentration-dependent manner, inhibited the evoked release of acetylcholine in the ventral, but not in the dorsal, hippocampus. Intracerebroventricularly applied galanin fully inhibited the scopolamine stimulated release of acetylcholine in the ventral, but not in the dorsal, hippocampus, as measured by the microdialysis technique. In vitro, galanin inhibited the 25 mM K/sup +/-evoked release of (/sup 3/H)acetylcholine from slices of the ventral hippocampus, with an IC/sub 50/ value of approx. = 50 nM. These results are discussed with respect to the colocalization of galanin- and choline acetyltransferase-like immunoreactivity in septal somata projecting to the hippocampus.

  2. Spatial representations in dorsal hippocampal neurons during a tactile-visual conditional discrimination task.

    PubMed

    Griffin, Amy L; Owens, Cullen B; Peters, Gregory J; Adelman, Peter C; Cline, Kathryn M

    2012-02-01

    Trajectory-dependent coding in dorsal CA1 of hippocampus has been evident in various spatial memory tasks aiming to model episodic memory. Hippocampal neurons are considered to be trajectory-dependent if the neuron has a place field located on an overlapping segment of two trajectories and exhibits a reliable difference in firing rate between the two trajectories. It is unclear whether trajectory-dependent coding in hippocampus is a mechanism used by the rat to solve spatial memory tasks. A first step in answering this question is to compare results between studies using tasks that require spatial working memory and those that do not. We recorded single units from dorsal CA1 of hippocampus during performance of a discrete-trial, tactile-visual conditional discrimination (CD) task in a T-maze. In this task, removable floor inserts that differ in texture and appearance cue the rat to visit either the left or right goal arm to receive a food reward. Our goal was to assess whether trajectory coding would be evident in the CD task. Our results show that trajectory coding was rare in the CD task, with only 12 of 71 cells with place fields on the maze stem showing a significant firing rate difference between left and right trials. For comparison, we recorded from dorsal CA1 during the acquisition and performance of a continuous spatial alternation task identical to that used in previous studies and found a proportion of trajectory coding neurons similar to what has been previously reported. Our data suggest that trajectory coding is not a universal mechanism used by the hippocampus to disambiguate similar trajectories, and instead may be more likely to appear in tasks that require the animal to retrieve information about a past trajectory, particularly in tasks that are continuous rather than discrete in nature.

  3. The rat brain hippocampus proteome.

    PubMed

    Fountoulakis, Michael; Tsangaris, George T; Maris, Antony; Lubec, Gert

    2005-05-05

    The hippocampus is crucial in memory storage and retrieval and plays an important role in stress response. In humans, the CA1 area of hippocampus is one of the first brain areas to display pathology in Alzheimer's disease. A comprehensive analysis of the hippocampus proteome has not been accomplished yet. We applied proteomics technologies to construct a two-dimensional database for rat brain hippocampus proteins. Hippocampus samples from eight months old animals were analyzed by two-dimensional electrophoresis and the proteins were identified by matrix-assisted laser desorption ionization time-of-flight mass spectrometry. The database comprises 148 different gene products, which are in the majority enzymes, structural proteins and heat shock proteins. It also includes 39 neuron specific gene products. The database may be useful in animal model studies of neurological disorders.

  4. Activity-based anorexia has differential effects on apical dendritic branching in dorsal and ventral hippocampal CA1.

    PubMed

    Chowdhury, Tara G; Barbarich-Marsteller, Nicole C; Chan, Thomas E; Aoki, Chiye

    2014-11-01

    Anorexia nervosa (AN) is an eating disorder to which adolescent females are particularly vulnerable. Like AN, activity-based anorexia (ABA), a rodent model of AN, results in elevation of stress hormones and has genetic links to anxiety disorders. The hippocampus plays a key role in the regulation of anxiety and responds with structural changes to hormones and stress, suggesting that it may play a role in AN. The hippocampus of ABA animals exhibits increased brain-derived neurotrophic factor and increased GABA receptor expression, but the structural effects of ABA have not been studied. We used Golgi staining of neurons to determine whether ABA in female rats during adolescence results in structural changes to the apical dendrites in hippocampal CA1 and contrasted to the effects of food restriction (FR) and exercise (EX), the environmental factors used to induce ABA. In the dorsal hippocampus, which preferentially mediates spatial learning and cognition, cells of ABA animals had less total dendritic length and fewer dendritic branches in stratum radiatum (SR) than in control (CON). In the ventral hippocampus, which preferentially mediates anxiety, ABA evoked more branching in SR than CON. In both dorsal and ventral regions, the main effect of exercise was localized to the SR while the main effect of food restriction occurred in the stratum lacunosum-moleculare. Taken together with data on spine density, these results indicate that ABA elicits pathway-specific changes in the hippocampus that may underlie the increased anxiety and reduced behavioral flexibility observed in ABA.

  5. Differential expression of molecular markers of synaptic plasticity in the hippocampus, prefrontal cortex, and amygdala in response to spatial learning, predator exposure, and stress-induced amnesia.

    PubMed

    Zoladz, Phillip R; Park, Collin R; Halonen, Joshua D; Salim, Samina; Alzoubi, Karem H; Srivareerat, Marisa; Fleshner, Monika; Alkadhi, Karim A; Diamond, David M

    2012-03-01

    We have studied the effects of spatial learning and predator stress-induced amnesia on the expression of calcium/calmodulin-dependent protein kinase II (CaMKII), brain-derived neurotrophic factor (BDNF) and calcineurin in the hippocampus, basolateral amygdala (BLA), and medial prefrontal cortex (mPFC). Adult male rats were given a single training session in the radial-arm water maze (RAWM) composed of 12 trials followed by a 30-min delay period, during which rats were either returned to their home cages or given inescapable exposure to a cat. Immediately following the 30-min delay period, the rats were given a single test trial in the RAWM to assess their memory for the hidden platform location. Under control (no stress) conditions, rats exhibited intact spatial memory and an increase in phosphorylated CaMKII (p-CaMKII), total CaMKII, and BDNF in dorsal CA1. Under stress conditions, rats exhibited impaired spatial memory and a suppression of all measured markers of molecular plasticity in dorsal CA1. The molecular profiles observed in the BLA, mPFC, and ventral CA1 were markedly different from those observed in dorsal CA1. Stress exposure increased p-CaMKII in the BLA, decreased p-CaMKII in the mPFC, and had no effect on any of the markers of molecular plasticity in ventral CA1. These findings provide novel observations regarding rapidly induced changes in the expression of molecular plasticity in response to spatial learning, predator exposure, and stress-induced amnesia in brainregions involved in different aspects of memory processing.

  6. Age-related deficit in behavioural extinction is counteracted by long-term ethanol consumption: correlation between 5-HIAA/5HT ratio in dorsal raphe nucleus and cognitive parameters.

    PubMed

    Oliveira-Silva, Ieda F; Pinto, Lucas; Pereira, Silvia R C; Ferraz, Vany P; Barbosa, Alfredo J A; Coelho, Vivian A A; Gualberto, Felipe F A S; Souza, Valeria F; Faleiro, Rosiane R M; Franco, Glaura C; Ribeiro, Angela M

    2007-06-18

    We investigated age-related changes in learning and memory performance and behavioural extinction in the water maze; and in endogenous levels of serotonin (5-HT) and 5-hydroxyindole acetic acid (5-HIAA) in the neocortex, hippocampus, thalamus and dorsal raphe nucleus of Wistar rats. Another aim was to assess the correlation between behavioural and biochemical parameters, which were measured in rodents of two different ages: 5 months (adults) and 16 months (middle-aged). The middle-aged subjects succeeded in learning the behavioural task, albeit with significantly worse performance when compared to adult animals. Aging also had significant main effects on memory and extinction. An age-dependent decrease in 5-HIAA levels was observed in both hippocampus and dorsal raphe nucleus (DRN). The decrease in DRN 5-HIAA was paralleled by a decrease in 5-HIAA/5-HT ratio in this brain area, which was significantly correlated to the animals' spatial memory performance and behavioural extinction. In addition, using middle-aged rats, a 2x2 factorial study was carried out to examine the effects of food restriction and chronic ethanol consumption on rat's performance in a spatial behavioural task and on central serotonergic parameters. None of these two treatments had a significant effect on the behavioural and biochemical parameters assessed, with the exception of extinction index, which was significantly affected by ethanol consumption. Long-term ethanol ameliorated the impairment in behavioural flexibility caused by aging. In conclusion, long-term ethanol consumption may have a role in protecting against age-related deficit in behavioural extinction. Moreover, the present results also indicate that DRN serotonergic system is involved in spatial memory and behavioural extinction.

  7. Dendritic GIRK channels gate the integration window, plateau potentials and induction of synaptic plasticity in dorsal but not ventral CA1 neurons.

    PubMed

    Malik, Ruchi; Johnston, Daniel

    2017-03-09

    Studies comparing neuronal activity at the dorsal and ventral poles of the hippocampus have shown that the scale of spatial information increases and the precision with which space is represented declines from the dorsal to ventral end. These dorsoventral differences in neuronal output and spatial representation could arise due to differences in computations performed by dorsal and ventral CA1 neurons. In this study, we tested this hypothesis by quantifying the differences in dendritic integration and synaptic plasticity between dorsal and ventral CA1 pyramidal neurons of rat hippocampus. Using a combination of somatic and dendritic patch clamp recordings, we show that the threshold for LTP induction is higher in dorsal CA1 neurons and that a G protein-coupled inward-rectifying potassium channel (GIRK) mediated regulation of dendritic plateau potentials and dendritic excitability underlies this gating. By contrast, similar regulation of LTP is absent in ventral CA1 neurons. Additionally, we show that generation of plateau potentials and LTP induction in dorsal CA1 neurons depends on the coincident activation of Schaffer collateral and temporoammonic inputs at the distal apical dendrites. The ventral CA1 dendrites, however, can generate plateau potentials in response to temporally dispersed excitatory inputs. Overall, our results highlight the dorsoventral differences in dendritic computation that could account for the dorsoventral differences in spatial representation.SIGNIFICANCE STATEMENTThe dorsal and ventral parts of the hippocampus encode spatial information at very different scales. While the place specific firing fields are small and precise at the dorsal end of the hippocampus, neurons at the ventral end have comparatively larger place fields. Here, we show that the dorsal CA1 neurons have a higher threshold for long-term potentiation (LTP) and require coincident timing of excitatory synaptic inputs for the generation of dendritic plateau potentials. By

  8. Gateways of ventral and dorsal streams in mouse visual cortex

    PubMed Central

    Wang, Quanxin; Gao, Enquan; Burkhalter, Andreas

    2011-01-01

    It is widely held that the spatial processing functions underlying rodent navigation are similar to those encoding human episodic memory (Doeller et al, 2010). Spatial and nonspatial information are provided by all senses including vision. It has been suggested that visual inputs are fed to the navigational network in cortex and hippocampus through dorsal and ventral intracortical streams (Whitlock et al, 2008), but this has not been shown directly in rodents. We have used cyto- and chemoarchitectonic markers, topographic mapping of receptive fields and pathway tracing to determine in mouse visual cortex whether the lateromedial (LM) and the anterolateral fields (AL), which are the principal targets of primary visual cortex (V1) (Wang and Burkhalter, 2007) specialized for processing nonspatial and spatial visual information (Gao et al, 2006), are distinct areas with diverse connections. We have found that the LM/AL border coincides with a change in type 2 muscarinic acetylcholine receptor (m2AChR) expression in layer 4 and with the representation of the lower visual field periphery. Our quantitative analyses further show that LM strongly projects to temporal cortex as well as the lateral entorhinal cortex, which has weak spatial selectivity (Hargreaves et al, 2005). In contrast, AL has stronger connections with posterior parietal cortex, motor cortex and the spatially selective medial entorhinal cortex (Haftig et al, 2005). These results support the notion that LM and AL are architecturally, topographically and connectionally distinct areas of extrastriate visual cortex and that they are gateways for ventral and dorsal streams. PMID:21289200

  9. Acute genistein treatment mimics the effects of estradiol by enhancing place learning and impairing response learning in young adult female rats.

    PubMed

    Pisani, Samantha L; Neese, Steven L; Doerge, Daniel R; Helferich, William G; Schantz, Susan L; Korol, Donna L

    2012-09-01

    Endogenous estrogens have bidirectional effects on learning and memory, enhancing or impairing cognition depending on many variables, including the task and the memory systems that are engaged. Moderate increases in estradiol enhance hippocampus-sensitive place learning, yet impair response learning that taps dorsal striatal function. This memory modulation likely occurs via activation of estrogen receptors, resulting in altered neural function. Supplements containing estrogenic compounds from plants are widely consumed despite limited information about their effects on brain function, including learning and memory. Phytoestrogens can enter the brain and signal through estrogen receptors to affect cognition. Enhancements in spatial memory and impairments in executive function have been found following treatment with soy phytoestrogens, but no tests of actions on striatum-sensitive tasks have been made to date. The present study compared the effects of acute exposure to the isoflavone genistein with the effects of estradiol on performance in place and response learning tasks. Long-Evans rats were ovariectomized, treated with 17β-estradiol benzoate, genistein-containing sucrose pellets, or vehicle (oil or plain sucrose pellets) for 2 days prior to behavioral training. Compared to vehicle controls, estradiol treatment enhanced place learning at a low (4.5 μg/kg) but not high dose (45 μg/kg), indicating an inverted pattern of spatial memory facilitation. Treatment with 4.4 mg of genistein over 2 days also significantly enhanced place learning over vehicle controls. For the response task, treatment with estradiol impaired learning at both low and high doses; likewise, genistein treatment impaired response learning compared to rats receiving vehicle. Overall, genistein was found to mimic estradiol-induced shifts in place and response learning, facilitating hippocampus-sensitive learning and slowing striatum-sensitive learning. These results suggest signaling through

  10. Aging hippocampus and amygdala.

    PubMed

    Malykhin, Nikolai V; Bouchard, Thomas P; Camicioli, Richard; Coupland, Nicholas J

    2008-03-26

    Earlier studies suggest that the anterior hippocampus may show resilience to age-associated volume loss. This study compared high-resolution magnetic resonance images obtained from younger (n=28; age range: 22-50 years) and older (n=39; age range: 65-84 years) healthy right-handed individuals to determine whether age-related volume changes varied between the hippocampal head, body and tail. Volumetric reductions were progressively more severe from hippocampal head to tail. Amygdala volume differences were intermediate in size. Although limited by the cross-sectional design, these data suggest that hippocampal subregions show a gradient of volume reduction in healthy aging that contrasts with the preferential reduction of anterior hippocampal volumes in Alzheimer's and Parkinson's diseases.

  11. [Correlation of evoked potentials in the frontal cortex and hippocampus of cats in emotional stress].

    PubMed

    Vanetsian, G L; Pavlova, I V

    2002-01-01

    Averaged auditory evoked potentials (AEPs) were recorded in symmetric points of the frontal cortex and dorsal hippocampus of cats performing acquired conditioned food-procuring reaction reinforced in 100% cases, urgent transition to 30%-reinforcement, and return to 100%-reinforcement. Emotional stress estimated by a heart rate rise developed during increased food motivation of a cat as well as during change in ordinary food-procuring stereotype. The emotional stress was accompanied by a high positive correlation of cortical and hippocampal AEPs. Decrease in the stress level led to a drop between AEP correlations and appearance of their negative values. In emotional stress, the interactions between the frontal cortex and dorsal hippocampus were asymmetric: right-side correlations were higher.

  12. Nicotinic receptors, memory, and hippocampus.

    PubMed

    Kutlu, Munir Gunes; Gould, Thomas J

    2015-01-01

    Nicotinic acetylcholine receptors (nAChRs) modulate the neurobiological processes underlying hippocampal learning and memory. In addition, nicotine's ability to desensitize and upregulate certain nAChRs may alter hippocampus-dependent memory processes. Numerous studies have examined the effects of nicotine on hippocampus-dependent learning, as well as the roles of low- and high-affinity nAChRs in mediating nicotine's effects on hippocampus-dependent learning and memory. These studies suggested that while acute nicotine generally acts as a cognitive enhancer for hippocampus-dependent learning, withdrawal from chronic nicotine results in deficits in hippocampus-dependent memory. Furthermore, these studies demonstrated that low- and high-affinity nAChRs functionally differ in their involvement in nicotine's effects on hippocampus-dependent learning. In the present chapter, we reviewed studies using systemic or local injections of acute or chronic nicotine, nAChR subunit agonists or antagonists; genetically modified mice; and molecular biological techniques to characterize the effects of nicotine on hippocampus-dependent learning.

  13. Network Profiles of the Dorsal Anterior Cingulate and Dorsal Prefrontal Cortex in Schizophrenia During Hippocampal-Based Associative Memory

    PubMed Central

    Woodcock, Eric A.; Wadehra, Sunali; Diwadkar, Vaibhav A.

    2016-01-01

    Schizophrenia is a disorder characterized by brain network dysfunction, particularly during behavioral tasks that depend on frontal and hippocampal mechanisms. Here, we investigated network profiles of the regions of the frontal cortex during memory encoding and retrieval, phases of processing essential to associative memory. Schizophrenia patients (n = 12) and healthy control (HC) subjects (n = 10) participated in an established object-location associative memory paradigm that drives frontal-hippocampal interactions. Network profiles were modeled of both the dorsal prefrontal (dPFC) and the dorsal anterior cingulate cortex (dACC) as seeds using psychophysiological interaction analyses, a robust framework for investigating seed-based connectivity in specific task contexts. The choice of seeds was motivated by previous evidence of involvement of these regions during associative memory. Differences between patients and controls were evaluated using second-level analyses of variance (ANOVA) with seed (dPFC vs. dACC), group (patients vs. controls), and memory process (encoding and retrieval) as factors. Patients showed a pattern of exaggerated modulation by each of the dACC and the dPFC during memory encoding and retrieval. Furthermore, group by memory process interactions were observed within regions of the hippocampus. In schizophrenia patients, relatively diminished modulation during encoding was associated with increased modulation during retrieval. These results suggest a pattern of complex dysfunctional network signatures of critical forebrain regions in schizophrenia. Evidence of dysfunctional frontal-medial temporal lobe network signatures in schizophrenia is consistent with the illness’ characterization as a disconnection syndrome. PMID:27092063

  14. Network Profiles of the Dorsal Anterior Cingulate and Dorsal Prefrontal Cortex in Schizophrenia During Hippocampal-Based Associative Memory.

    PubMed

    Woodcock, Eric A; Wadehra, Sunali; Diwadkar, Vaibhav A

    2016-01-01

    Schizophrenia is a disorder characterized by brain network dysfunction, particularly during behavioral tasks that depend on frontal and hippocampal mechanisms. Here, we investigated network profiles of the regions of the frontal cortex during memory encoding and retrieval, phases of processing essential to associative memory. Schizophrenia patients (n = 12) and healthy control (HC) subjects (n = 10) participated in an established object-location associative memory paradigm that drives frontal-hippocampal interactions. Network profiles were modeled of both the dorsal prefrontal (dPFC) and the dorsal anterior cingulate cortex (dACC) as seeds using psychophysiological interaction analyses, a robust framework for investigating seed-based connectivity in specific task contexts. The choice of seeds was motivated by previous evidence of involvement of these regions during associative memory. Differences between patients and controls were evaluated using second-level analyses of variance (ANOVA) with seed (dPFC vs. dACC), group (patients vs. controls), and memory process (encoding and retrieval) as factors. Patients showed a pattern of exaggerated modulation by each of the dACC and the dPFC during memory encoding and retrieval. Furthermore, group by memory process interactions were observed within regions of the hippocampus. In schizophrenia patients, relatively diminished modulation during encoding was associated with increased modulation during retrieval. These results suggest a pattern of complex dysfunctional network signatures of critical forebrain regions in schizophrenia. Evidence of dysfunctional frontal-medial temporal lobe network signatures in schizophrenia is consistent with the illness' characterization as a disconnection syndrome.

  15. Encoding and reactivation patterns predictive of successful memory performance are topographically organized along the longitudinal axis of the hippocampus.

    PubMed

    Nakamura, Nozomu H; Sauvage, Magdalena M

    2016-01-01

    An ongoing debate in human memory research is whether the encoding and the retrieval of memory engage the same part of the hippocampus and the same cells, or whether encoding preferentially involves the anterior part of the hippocampus and retrieval its posterior part. Here, we used a human to rat translational behavioral approach combined to high-resolution molecular imaging to address this issue. We showed that successful memory performance is predicted by encoding and reactivation patterns only in the dorsal part of the rat hippocampus (posterior part in humans), but not in the ventral part (anterior part in humans). Our findings support the view that the encoding and the retrieval processes per se are not segregated along the longitudinal axis of the hippocampus, but that activity predictive of successful memory is and concerns specifically the dorsal part of the hippocampus. In addition, we found evidence that these processes are likely to be mediated by the activation/reactivation of the same cells at this level. Given the translational character of the task, our results suggest that both the encoding and the retrieval processes take place in the same cells of the posterior part of the human hippocampus.

  16. IL-1 receptor antagonist attenuates neonatal lipopolysaccharide-induced long-lasting learning impairment and hippocampal injury in adult rats

    PubMed Central

    Pang, Yi; Bhatt, Abhay J.; Fan, Lir-Wan

    2015-01-01

    We have previously reported that neonatal lipopolysaccharide (LPS) exposure resulted in an increase in interleukin-1β (IL-1β) content, injury to the hippocampus, and cognitive deficits in juvenile male and female rats, as well as female adult rats. The present study aimed to determine whether an antiinflammatory cytokine, interleukin-1 receptor antagonist (IL-1ra), protects against the neonatal LPS exposure-induced inflammatory responses, hippocampal injury, and long-lasting learning deficits in adult rats. LPS (1 mg/kg) or LPS plus IL-1ra (0.1 mg/kg) was injected intracerebrally to Sprague-Dawley male rat pups at postnatal day 5 (P5). Neurobehavioral tests were carried out on P21, P49, and P70, while neuropathological studies were conducted on P71. Our results showed that neonatal LPS exposure resulted in learning deficits in rats at both developmental and adult ages, as demonstrated by a significantly impaired performance in the passive avoidance task (P21, P49, and P70), reduced hippocampal volume, and reduced number of Nissl+ cells in the CA1 region of the middle dorsal hippocampus of P71 rat brain. Those neuropathological and neurobehavioral alterations by LPS exposure were associated with a sustained inflammatory response in the P71 rat hippocampus, indicated by increased number of activated microglia as well as elevated levels of IL-1β. Neonatal administration of IL-1ra significantly attenuated LPS-induced long-lasting learning deficits, hippocampal injury, and sustained inflammatory responses in P71 rats. Our study demonstrates that neonatal LPS exposure leads to a persistent injury to the hippocampus, resulting in long-lasting learning disabilities related to chronic inflammation in rats, and these effects can be attenuated with an IL-1 receptor antagonist. PMID:25665855

  17. IL-1 receptor antagonist attenuates neonatal lipopolysaccharide-induced long-lasting learning impairment and hippocampal injury in adult rats.

    PubMed

    Lan, Kuo-Mao; Tien, Lu-Tai; Pang, Yi; Bhatt, Abhay J; Fan, Lir-Wan

    2015-04-02

    We have previously reported that neonatal lipopolysaccharide (LPS) exposure resulted in an increase in interleukin-1β (IL-1β) content, injury to the hippocampus, and cognitive deficits in juvenile male and female rats, as well as female adult rats. The present study aimed to determine whether an anti-inflammatory cytokine, interleukin-1 receptor antagonist (IL-1ra), protects against the neonatal LPS exposure-induced inflammatory responses, hippocampal injury, and long-lasting learning deficits in adult rats. LPS (1 mg/kg) or LPS plus IL-1ra (0.1 mg/kg) was injected intracerebrally to Sprague-Dawley male rat pups at postnatal day 5 (P5). Neurobehavioral tests were carried out on P21, P49, and P70, while neuropathological studies were conducted on P71. Our results showed that neonatal LPS exposure resulted in learning deficits in rats at both developmental and adult ages, as demonstrated by a significantly impaired performance in the passive avoidance task (P21, P49, and P70), reduced hippocampal volume, and reduced number of Nissl+ cells in the CA1 region of the middle dorsal hippocampus of P71 rat brain. Those neuropathological and neurobehavioral alterations by LPS exposure were associated with a sustained inflammatory response in the P71 rat hippocampus, indicated by increased number of activated microglia as well as elevated levels of IL-1β. Neonatal administration of IL-1ra significantly attenuated LPS-induced long-lasting learning deficits, hippocampal injury, and sustained inflammatory responses in P71 rats. Our study demonstrates that neonatal LPS exposure leads to a persistent injury to the hippocampus, resulting in long-lasting learning disabilities related to chronic inflammation in rats, and these effects can be attenuated with an IL-1 receptor antagonist.

  18. Role of the thalamic nucleus reuniens in mediating interactions between the hippocampus and medial prefrontal cortex during spatial working memory.

    PubMed

    Griffin, Amy L

    2015-01-01

    Despite decades of research, the neural mechanisms of spatial working memory remain poorly understood. Although the dorsal hippocampus is known to be critical for memory-guided behavior, experimental evidence suggests that spatial working memory depends not only on the hippocampus itself, but also on the circuit comprised of the hippocampus and the medial prefrontal cortex (mPFC). Disruption of hippocampal-mPFC interactions may result in failed transfer of spatial and contextual information processed by the hippocampus to the circuitry in mPFC responsible for decision making and goal-directed behavior. Oscillatory synchrony between the hippocampus and mPFC has been shown to increase in tasks with high spatial working memory demand. However, the mechanisms and circuitry supporting hippocampal-mPFC interactions during these tasks is unknown. The midline thalamic nucleus reuniens (RE) is reciprocally connected to both the hippocampus and the mPFC and has been shown to be critical for a variety of working memory tasks. Therefore, it is likely that hippocampal-mPFC oscillatory synchrony is modulated by RE activity. This article will review the anatomical connections between the hippocampus, mPFC and RE along with the behavioral studies that have investigated the effects of RE disruption on working memory task performance. The article will conclude with suggestions for future directions aimed at identifying the specific role of the RE in regulating functional interactions between the hippocampus and the PFC and investigating the degree to which these interactions contribute to spatial working memory.

  19. Regional-specific effect of fluoxetine on rapidly dividing progenitors along the dorsoventral axis of the hippocampus

    PubMed Central

    Zhou, Qi-Gang; Lee, Daehoon; Ro, Eun Jeoung; Suh, Hoonkyo

    2016-01-01

    Hippocampus-dependent cognitive and emotional function appears to be regionally dissociated along the dorsoventral (DV) axis of the hippocampus. Recent observations that adult hippocampal neurogenesis plays a critical role in both cognition and emotion raised an interesting question whether adult neurogenesis within specific subregions of the hippocampus contributes to these distinct functions. We examined the regional-specific and cell type-specific effects of fluoxetine, which requires adult hippocampal neurogenesis to function as an antidepressant, on the proliferation of hippocampal neural stem cells (NSCs). Fluoxetine specifically increased proliferation of NSCs located in the ventral region of the hippocampus while the mitotic index of NSCs in the dorsal portion of the hippocampus remained unaltered. Moreover, within the ventral hippocampus, type II NSC and neuroblast populations specifically responded to fluoxetine, showing increased proliferation; however, proliferation of type I NSCs was unchanged in response to fluoxetine. Activation or inhibition of serotonin receptor 1A (5-HTR1A) recapitulated or abolished the effect of fluoxetine on proliferation of type II NSCs and neuroblast populations in the ventral hippocampus. Our study showed that the effect of fluoxetine on proliferation is dependent upon the type and the position of the NSCs along the DV axis of the hippocampus. PMID:27759049

  20. A fundamental oscillatory state of isolated rodent hippocampus.

    PubMed

    Wu, Chiping; Shen, Hui; Luk, Wah Ping; Zhang, Liang

    2002-04-15

    Population neuronal rhythms of various frequencies are observed in the rodent hippocampus during distinct behavioural states. However, the question of whether the hippocampus exhibits properties of spontaneous rhythms and population synchrony in isolation has not been definitively answered. To address this, we developed a novel preparation for studying neuronal rhythms in a relatively large hippocampal tissue in vitro. We isolated the whole hippocampus from mice up to 28 days postnatal age, removing the dentate gyrus while preserving the functional CA3-to-CA1 connections. Placing the hippocampal isolate in a perfusion chamber for electrophysiological assessment extracellular recordings from the CA1 revealed rhythmic field potential of 0.5 to dorsal hippocampal axis. We provide convergent evidence, via measurements of extracellular pH and K(+), recordings of synaptic and intracellular activities and morphological assessments, verifying that these rhythms were not the consequence of hypoxia. Data obtained via simultaneous extracellular and patch clamp recordings suggest that the spontaneous rhythms represent a summation of GABAergic IPSPs originating from pyramidal neurons, which result from synchronous discharges of GABAergic inhibitory interneurons. Similar spontaneous field rhythms were also observed in the hippocampal isolate prepared from young gerbils and rats. Based on these data, we postulate that the spontaneous rhythms represent a fundamental oscillatory state of the hippocampal circuitry isolated from extra-hippocampal inputs.

  1. A fundamental oscillatory state of isolated rodent hippocampus

    PubMed Central

    Wu, Chiping; Shen, Hui; Luk, Wah Ping; Zhang, Liang

    2002-01-01

    Population neuronal rhythms of various frequencies are observed in the rodent hippocampus during distinct behavioural states. However, the question of whether the hippocampus exhibits properties of spontaneous rhythms and population synchrony in isolation has not been definitively answered. To address this, we developed a novel preparation for studying neuronal rhythms in a relatively large hippocampal tissue in vitro. We isolated the whole hippocampus from mice up to 28 days postnatal age, removing the dentate gyrus while preserving the functional CA3-to-CA1 connections. Placing the hippocampal isolate in a perfusion chamber for electrophysiological assessment extracellular recordings from the CA1 revealed rhythmic field potential of 0.5 to ≤ 4 Hz that occurred spontaneously and propagated along the ventro-dorsal hippocampal axis. We provide convergent evidence, via measurements of extracellular pH and K+, recordings of synaptic and intracellular activities and morphological assessments, verifying that these rhythms were not the consequence of hypoxia. Data obtained via simultaneous extracellular and patch clamp recordings suggest that the spontaneous rhythms represent a summation of GABAergic IPSPs originating from pyramidal neurons, which result from synchronous discharges of GABAergic inhibitory interneurons. Similar spontaneous field rhythms were also observed in the hippocampal isolate prepared from young gerbils and rats. Based on these data, we postulate that the spontaneous rhythms represent a fundamental oscillatory state of the hippocampal circuitry isolated from extra-hippocampal inputs. PMID:11956340

  2. The maintenance of long-term memory in the hippocampus depends on the interaction between N-ethylmaleimide-sensitive factor and GluA2.

    PubMed

    Migues, Paola Virginia; Hardt, Oliver; Finnie, Peter; Wang, Yu Wang; Nader, Karim

    2014-09-01

    The maintenance of established memories has recently been shown to involve the stabilization of GluA2-containing AMPA receptors (GluA2/AMPARs) at postsynaptic membranes. Previous studies have suggested that N-ethylmaleimide-sensitive factor (NSF) regulates the stabilization of AMPARs at the synaptic membrane. We therefore disrupted the interaction between GluA2 and NSF in the dorsal hippocampus and examined its effect on the maintenance of object location and contextual fear memory. We used two interference peptides, pep2m and pepR845A, that have been shown to block the binding of NSF to GluA2 and reduce GluA2 synaptic content. Either peptide disrupted consolidated memory, and these effects persisted for at least 5 or 28 days after peptide administration. Following peptide administration and long-term memory disruption, rats were able to acquire new memories. Memory acquisition or consolidation was not impaired when pepR845A was given immediately before the training sessions. Blocking GluA2 endocytosis with the peptide GluA23Y prevented the memory impairment effect of pepR845A. Taken together, our results indicate that the persistence of long-term memory depends on the maintenance of a steady-state level of synaptic GluA2/AMPARs, which requires the interaction of NSF with GluA2.

  3. The effect of insulin and insulin-like growth factors on hippocampus- and amygdala-dependent long-term memory formation.

    PubMed

    Stern, Sarah A; Chen, Dillon Y; Alberini, Cristina M

    2014-10-01

    Recent work has reported that the insulin-like growth factor 2 (IGF2) promotes memory enhancement. Furthermore, impaired insulin or IGF1 functions have been suggested to play a role in the pathogenesis of neurodegeneration and cognitive impairments, hence implicating the insulin/IGF system as an important target for cognitive enhancement and/or the development of novel treatments against cognitive disorders. Here, we tested the effect of intracerebral injections of IGF1, IGF2, or insulin on memory consolidation and persistence in rats. We found that a bilateral injection of insulin into the dorsal hippocampus transiently enhances hippocampal-dependent memory and an injection of IGF1 has no effect. None of the three peptides injected into the amygdala affected memories critically engaging this region. Together with previous data on IGF2, these results indicate that IGF2 produces the most potent and persistent effect as a memory enhancer on hippocampal-dependent memories. We suggest that the memory-enhancing effects of insulin and IGF2 are likely mediated by distinct mechanisms.

  4. The effect of insulin and insulin-like growth factors on hippocampus- and amygdala-dependent long-term memory formation

    PubMed Central

    Stern, Sarah A.; Chen, Dillon Y.

    2014-01-01

    Recent work has reported that the insulin-like growth factor 2 (IGF2) promotes memory enhancement. Furthermore, impaired insulin or IGF1 functions have been suggested to play a role in the pathogenesis of neurodegeneration and cognitive impairments, hence implicating the insulin/IGF system as an important target for cognitive enhancement and/or the development of novel treatments against cognitive disorders. Here, we tested the effect of intracerebral injections of IGF1, IGF2, or insulin on memory consolidation and persistence in rats. We found that a bilateral injection of insulin into the dorsal hippocampus transiently enhances hippocampal-dependent memory and an injection of IGF1 has no effect. None of the three peptides injected into the amygdala affected memories critically engaging this region. Together with previous data on IGF2, these results indicate that IGF2 produces the most potent and persistent effect as a memory enhancer on hippocampal-dependent memories. We suggest that the memory-enhancing effects of insulin and IGF2 are likely mediated by distinct mechanisms. PMID:25227250

  5. Context conditioning and extinction in humans: differential contribution of the hippocampus, amygdala and prefrontal cortex

    PubMed Central

    Lang, Simone; Kroll, Alexander; Lipinski, Slawomira J; Wessa, Michèle; Ridder, Stephanie; Christmann, Christoph; Schad, Lothar R; Flor, Herta

    2009-01-01

    Functional magnetic resonance imaging was used to investigate the role of the hippocampus, amygdala and medial prefrontal cortex (mPFC) in a contextual conditioning and extinction paradigm provoking anxiety. Twenty-one healthy persons participated in a differential context conditioning procedure with two different background colours as contexts. During acquisition increased activity to the conditioned stimulus (CS+) relative to the CS− was found in the left hippocampus and anterior cingulate cortex (ACC). The amygdala, insula and inferior frontal cortex were differentially active during late acquisition. Extinction was accompanied by enhanced activation to CS+ vs. CS− in the dorsal anterior cingulate cortex (dACC). The results are in accordance with animal studies and provide evidence for the important role of the hippocampus in contextual learning in humans. Connectivity analyses revealed correlated activity between the left posterior hippocampus and dACC (BA32) during early acquisition and the dACC, left posterior hippocampus and right amygdala during extinction. These data are consistent with theoretical models that propose an inhibitory effect of the mPFC on the amygdala. The interaction of the mPFC with the hippocampus may reflect the context-specificity of extinction learning. PMID:19200075

  6. Late-Onset Cognitive Impairments after Early-Life Stress Are Shaped by Inherited Differences in Stress Reactivity

    PubMed Central

    McIlwrick, Silja; Pohl, Tobias; Chen, Alon; Touma, Chadi

    2017-01-01

    Early-life stress (ELS) has been associated with lasting cognitive impairments and with an increased risk for affective disorders. A dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis, the body’s main stress response system, is critically involved in mediating these long-term consequences of adverse early-life experience. It remains unclear to what extent an inherited predisposition for HPA axis sensitivity or resilience influences the relationship between ELS and cognitive impairments, and which neuroendocrine and molecular mechanisms may be involved. To investigate this, we exposed animals of the stress reactivity mouse model, consisting of three independent lines selectively bred for high (HR), intermediate (IR), or low (LR) HPA axis reactivity to a stressor, to ELS and assessed their cognitive performance, neuroendocrine function and hippocampal gene expression in early and in late adulthood. Our results show that HR animals that were exposed to ELS exhibited an HPA axis hyper-reactivity in early and late adulthood, associated with cognitive impairments in hippocampus-dependent tasks, as well as molecular changes in transcript levels involved in the regulation of HPA axis activity (Crh) and in neurotrophic action (Bdnf). In contrast, LR animals showed intact cognitive function across adulthood, with no change in stress reactivity. Intriguingly, LR animals that were exposed to ELS even showed significant signs of enhanced cognitive performance in late adulthood, which may be related to late-onset changes observed in the expression of Crh and Crhr1 in the dorsal hippocampus of these animals. Collectively, our findings demonstrate that the lasting consequences of ELS at the level of cognition differ as a function of inherited predispositions and suggest that an innate tendency for low stress reactivity may be protective against late-onset cognitive impairments after ELS. PMID:28261058

  7. Painful laser stimuli induce directed functional interactions within and between the human amygdala and hippocampus

    PubMed Central

    Liu, C.C.; Shi, C-Q; Franaszczuk, P.J.; Crone, N.E.; Schretlen, D.; Ohara, S.; Lenz, F.A.

    2011-01-01

    The pathways by which painful stimuli are signaled within the human medial temporal lobe are unknown. Rodent studies have shown that nociceptive inputs are transmitted from the brainstem or thalamus through one of two pathways to the central nucleus of the amygdala. The indirect pathway projects from the basal and lateral nuclei of the amygdala to the central nucleus, while the direct pathway projects directly to the central nucleus. We now test the hypothesis that the human ventral amygdala (putative basal and lateral nuclei) exerts a causal influence upon the dorsal amygdala (putative central nucleus), during the application of a painful laser stimulus. Local field potentials (LFPs) were recorded from depth electrode contacts implanted in the medial temporal lobe for the treatment of epilepsy, and causal influences were analyzed by Granger causality (GRC). This analysis indicates that the dorsal amygdala exerts a pre-stimulus causal influence upon the hippocampus, consistent with an attention-related response to the painful laser. Within the amygdala, the analysis indicates that the ventral contacts exert a causal influence upon dorsal contacts, consistent with the human (putative) indirect pathway. Potentials evoked by the laser (LEPs) were not recorded in the ventral nuclei, but were recorded at dorsal amygdala contacts which were not preferentially those receiving causal influences from the ventral contacts. Therefore, it seems likely that the putative indirect pathway is associated with causal influences from the ventral to the dorsal amygdala, and is distinct from the human (putative) indirect pathway which mediates LEPs in the dorsal amygdala. PMID:21256929

  8. The Role of Dorsal Hippocampal Dopamine D1-Type Receptors in Social Learning, Social Interactions, and Food Intake in Male and Female Mice.

    PubMed

    Matta, Richard; Tiessen, Angela N; Choleris, Elena

    2017-03-29

    The neurobiological mechanisms underlying social learning (ie, in which an animal's learning is influenced by another) are slowly being unraveled. Previous work with systemic treatments shows that dopamine (DA) D1-type receptors mediate social learning in the social transmission of food preferences (STFP) in mice. This study examines the involvement of one brain region underlying this effect. The ventral tegmental area has dopaminergic projections to many limbic structures, including the hippocampus-a site important for social learning in the STFP in rodents. In this study, adult male and female CD-1 mice received a dorsal hippocampal microinfusion of the D1-like receptor antagonist SCH23390 at 1, 2, 4, or 6 μg/μl 15 min before a 30 min social interaction with a same-sex conspecific, in which mice had the opportunity to learn a socially transmitted food preference. Results show that social learning was blocked in female mice microinfused with 6 μg/μl, and in males infused with 1, 4, or 6 μg/μl of SCH23390. This social learning impairment could not be explained by changes in total food intake, or olfactory discrimination. A detailed analysis of the social interactions also revealed that although SCH23390 did not affect oronasal investigation for either sex, drug treatments affected other social behaviors in a sex-specific manner; there was primarily a reduction in agonistic-related behaviors among males, and social investigatory-related behaviors among females. Thus, this study shows that dorsal hippocampal D1-type receptors mediate social learning and social behaviors in male and female mice.Neuropsychopharmacology advance online publication, 29 March 2017; doi:10.1038/npp.2017.43.

  9. Memory, scene construction, and the human hippocampus

    PubMed Central

    Kim, Soyun; Dede, Adam J. O.; Hopkins, Ramona O.; Squire, Larry R.

    2015-01-01

    We evaluated two different perspectives about the function of the human hippocampus–one that emphasizes the importance of memory and another that emphasizes the importance of spatial processing and scene construction. We gave tests of boundary extension, scene construction, and memory to patients with lesions limited to the hippocampus or large lesions of the medial temporal lobe. The patients were intact on all of the spatial tasks and impaired on all of the memory tasks. We discuss earlier studies that associated performance on these spatial tasks to hippocampal function. Our results demonstrate the importance of medial temporal lobe structures for memory and raise doubts about the idea that these structures have a prominent role in spatial cognition. PMID:25825712

  10. Eszopiclone and fluoxetine enhance the survival of newborn neurons in the adult rat hippocampus.

    PubMed

    Su, Xiaowei W; Li, Xiao-Yuan; Banasr, Mounira; Duman, Ronald S

    2009-11-01

    Clinical research has shown that co-administration of eszopiclone, a sedative-hypnotic sleeping agent, and fluoxetine, a serotonin uptake inhibitor, exerts an additive antidepressant action in treating patients with both depression and insomnia. Preclinical studies demonstrate that the behavioural actions of antidepressants are linked to neurogenesis in the adult hippocampus. To test the hypothesis that the additive effects of eszopiclone and fluoxetine could act via such a mechanism, the influence of combined administration of these agents on the proliferation and survival of bromodeoxyuridine (BrdU)-labelled newborn cells in the hippocampus of adult rats was determined. Chronic eszopiclone+fluoxetine co-administration significantly increased the survival, but not proliferation, of newborn neurons in dorsal hippocampus by approximately 50%, an effect greater than either drug alone. These findings are consistent with the hypothesis that eszopiclone enhances the antidepressant action of fluoxetine, in part via a novel mechanism that increases the survival of newborn neurons.

  11. Electrophysiological Properties of CA1 Pyramidal Neurons along the Longitudinal Axis of the Mouse Hippocampus

    PubMed Central

    Milior, Giampaolo; Castro, Maria Amalia Di; Sciarria, Livio Pepe’; Garofalo, Stefano; Branchi, Igor; Ragozzino, Davide; Limatola, Cristina; Maggi, Laura

    2016-01-01

    Evidence for different physiological properties along the hippocampal longitudinal axis is emerging. Here, we examined the electrophysiological features of neurons at different dorso-ventral sites of the mouse CA1 hippocampal region. Cell position was defined with respect to longitudinal coordinates of each slice. We measured variations in neuronal excitability, subthreshold membrane properties and neurotransmitter responses along the longitudinal axis. We found that (i) pyramidal cells of the dorsal hippocampus (DH) were less excitable than those of the ventral hippocampus (VH). Resting Membrane Potential (RMP) was more hyperpolarized and somatic Input Resistance (Ri) was lower in DH compared to VH. (ii) The Paired-pulse ratio (PPR) of focally induced synaptic responses was systematically reduced from the DH to the VH; (iii) Long-term-potentiation was most pronounced in the DH and fell gradually in the intermediate hippocampus and in the VH; (iv) the frequency of miniature GABAergic events was higher in the VH than in the DH; (v) the PPR of evoked inhibitory post-synaptic current (IPSC) was higher in the DH than in the VH. These findings indicate an increased probability of both GABA and glutamate release and a reduced plasticity in the ventral compared to more dorsal regions of the hippocampus. PMID:27922053

  12. Liposarcome dorsal: aspect clinique rare

    PubMed Central

    Agbessi, Odry; Arrob, Adil; Fiqhi, Kamal; Khalfi, Lahcen; Nassih, Mohammed; El Khatib, Karim

    2015-01-01

    Décrit la première fois par Virchow en 1860, le liposarcome est une tumeur mésenchymateuse rare. Cette rareté est relative car les liposarcomes représentent quand même 14 à 18% de l'ensemble des tumeurs malignes des parties molles et ils constituent le plus fréquent des sarcomes des parties molles. Pour la majorité des auteurs, il ne se développerait jamais sur un lipome ou une lipomatose préexistant. Nous rapportons un cas de volumineux liposarcome de la face dorsale du tronc. L'histoire de la maladie, l'aspect clinique inhabituel « de tumeur dans tumeur », l'aspect de la pièce opératoire nous fait évoquer la possibilité de la transformation maligne d'un lipome bénin préexistant. PMID:26113914

  13. Molecular mechanisms involved in interleukin 1-beta (IL-1β)-induced memory impairment. Modulation by alpha-melanocyte-stimulating hormone (α-MSH).

    PubMed

    Gonzalez, P; Machado, I; Vilcaes, A; Caruso, C; Roth, G A; Schiöth, H; Lasaga, M; Scimonelli, T

    2013-11-01

    Pro-inflammatory cytokines can affect cognitive processes such as learning and memory. Particularly, interleukin-1β (IL-1β) influences the consolidation of hippocampus-dependent memories. We previously reported that administration of IL-1β in dorsal hippocampus impaired contextual fear memory consolidation. Different mechanisms have been implicated in the action of IL-1β on long-term potentiation (LTP), but the processes by which this inhibition occurs in vivo remain to be elucidated. We herein report that intrahippocampal injection of IL-1β induced a significant increase in p38 phosphorylation after contextual fear conditioning. Also, treatment with SB203580, an inhibitor of p38, reversed impairment induced by IL-1β on conditioned fear behavior, indicating that this MAPK would be involved in the effect of the cytokine. We also showed that IL-1β administration produced a decrease in glutamate release from dorsal hippocampus synaptosomes and that treatment with SB203580 partially reversed this effect. Our results indicated that IL-1β-induced impairment in memory consolidation could be mediated by a decrease in glutamate release. This hypothesis is sustained by the fact that treatment with d-cycloserine (DCS), a partial agonist of the NMDA receptor, reversed the effect of IL-1β on contextual fear memory. Furthermore, we demonstrated that IL-1β produced a temporal delay in ERK phosphorylation and that DCS administration reversed this effect. We also observed that intrahippocampal injection of IL-1β decreased BDNF expression after contextual fear conditioning. We previously demonstrated that α-MSH reversed the detrimental effect of IL-1β on memory consolidation. The present results demonstrate that α-MSH administration did not modify the decrease in glutamate release induced by IL-1β. However, intrahippocampal injection of α-MSH prevented the effect on ERK phosphorylation and BDNF expression induced by IL-1β after contextual fear conditioning

  14. Glucocorticoid effects on memory retrieval require concurrent noradrenergic activity in the hippocampus and basolateral amygdala.

    PubMed

    Roozendaal, Benno; Hahn, Emily L; Nathan, Sheila V; de Quervain, Dominique J-F; McGaugh, James L

    2004-09-15

    Previous findings indicate that administration of abeta-adrenoceptor antagonist systemically blocks glucocorticoid impairment of memory retrieval. Here, we report that beta-adrenoceptor activation in the hippocampus and the basolateral complex of the amygdala (BLA) is implicated in the impairing effects of glucocorticoids on memory retrieval. The specific glucocorticoid receptor (GR) agonist 11beta,17beta-dihydroxy-6,21-dimethyl-17alpha-pregna-4,6-trien-20yn-3-one (RU 28362) (15 ng) infused into the hippocampus of male Sprague Dawley rats 60 min before water maze retention testing, 24 hr after training, impaired probe trial retention performance, as assessed by quadrant search time and initial latency to cross the platform location. Because we found previously that RU 28362 infused into the hippocampus does not affect water maze acquisition or immediate recall, the findings suggest that the GR agonist-induced retention impairment was attributable to a selective influence on long-term memory retrieval. Likewise, systemic injections of the beta1-adrenoceptor partial agonist xamoterol (3.0 or 10.0 mg/kg, s.c.) 60 min before the probe trial dose-dependently impaired retention performance. The beta-adrenoceptor antagonist propranolol (2.0 mg/kg) administered subcutaneously before retention testing did not affect retention performance alone, but blocked the memory retrieval impairment induced by concurrent intrahippocampal infusions of RU 28362. Pretest infusions of the beta1-adrenoceptor antagonist atenolol into either the hippocampus (1.25 microg in 0.5 microl) or the BLA (0.5 microg in 0.2 microl) also prevented the GR agonist-induced memory retrieval impairment. These findings suggest that glucocorticoids impair retrieval of long-term spatial memory by facilitating noradrenergic mechanisms in the hippocampus, and additionally, that norepinephrine-mediated BLA activity is critical in enabling hippocampal glucocorticoid effects on memory retrieval.

  15. Fibroblast Growth Factor 22 Contributes to the Development of Retinal Nerve Terminals in the Dorsal Lateral Geniculate Nucleus

    PubMed Central

    Singh, Rishabh; Su, Jianmin; Brooks, Justin; Terauchi, Akiko; Umemori, Hisashi; Fox, Michael A.

    2012-01-01

    At least three forms of signaling between pre- and postsynaptic partners are necessary during synapse formation. First, “targeting” signals instruct presynaptic axons to recognize and adhere to the correct portion of a postsynaptic target cell. Second, trans-synaptic “organizing” signals induce differentiation in their synaptic partner so that each side of the synapse is specialized for synaptic transmission. Finally, in many regions of the nervous system an excess of synapses are initially formed, therefore “refinement” signals must either stabilize or destabilize the synapse to reinforce or eliminate connections, respectively. Because of both their importance in processing visual information and their accessibility, retinogeniculate synapses have served as a model for studying synaptic development. Molecular signals that drive retinogeniculate “targeting” and “refinement” have been identified, however, little is known about what “organizing” cues are necessary for the differentiation of retinal axons into presynaptic terminals. To identify such “organizing” cues, we used microarray analysis to assess whether any target-derived “synaptic organizers” were enriched in the mouse dorsal lateral geniculate nucleus (dLGN) during retinogeniculate synapse formation. One candidate “organizing” molecule enriched in perinatal dLGN was FGF22, a secreted cue that induces the formation of excitatory nerve terminals in muscle, hippocampus, and cerebellum. In FGF22 knockout mice, the development of retinal terminals in dLGN was impaired. Thus, FGF22 is an important “organizing” cue for the timely development of retinogeniculate synapses. PMID:22363257

  16. [Electrical activities of bursting-firing neurons in epileptic network reestablishment of rat hippocampus].

    PubMed

    Wang, Wen-Ting; Qin, Xing-Kui; Yin, Shi-Jin; Han, Dan

    2003-12-25

    The purpose of our present work was to study the discharge of bursting-firing neurons (BFNs) in ipsilateral or contralateral hippocampus (HPC), and its relations to the reestablishment of local epileptic networks. The experiments were performed on 140 Sprague Dawley male rats (150-250 g). Acute tetanization (60 Hz, 2 s, 0.4 -0.6 mA) of the right posterior dorsal hippocampus (ATPDH) was administered to establish rat epilepsy model. The single unit discharges and the depth electrographs were simultaneously recorded from ipsilateral or contralateral HPC. In other experimental rats, acute tetanization of the right anterior dorsal HPC (ATADH) was used. Extracellular unit discharges in the CA1 region were simultaneously recorded from bilateral anterior dorsal hippocampi. Analysis of hippocampal BFN firing patterns before or after administration of the tetanization was focused on according to their location in the HPC epileptic networks in vivo. Single unit discharges of 138 hippocampal neurons were recorded from ipsilateral and/or contralateral anterior dorsal HPC. Of the 138 neurons recorded, 19 were BFNs. 13 BFNs were tetanus-evoked and the remaining 6 were spontaneous ones. The evoked reactions of the single hippocampal neuron induced by the tetanization mainly included: (1) the firing patterns of the BFNs in ipsilateral anterior dorsal HPC were obviously modulated by the ATPDH from tonic firing into rhythmic bursting. The bursting interspike intervals (BISI) decreased. (2) There were mild modulations of the firing patterns of the BFNs in contralateral anterior dorsal HPC following post-inhibition of the firing rate of single neuron induced by the ATPDH. The interspike intervals (ISI) increased obviously. (3) Post-facilitation of rhythmic bursting-firing of the BFNs in contralateral anterior dorsal HPC was induced by ATADH; both the ISI and the IBI increased. (4) Synchronous or asynchronous rhythmic bursting-firing of the BFNs and the network epileptiform events

  17. Impaired retention of spatial memory after transection of longitudinally oriented axons of hippocampal CA3 pyramidal cells

    NASA Astrophysics Data System (ADS)

    Steffenach, Hill-Aina; Sloviter, Robert S.; Moser, Edvard I.; Moser, May-Britt

    2002-03-01

    Longitudinally oriented axon collaterals of CA3 pyramidal cells may be critical for integrating distributed information in the hippocampus. To investigate the possible role of this pathway in the retention of spatial memory, we made a single transversely oriented cut through the dorsal CA3 region of each hippocampus. Although the lesion involved <3% of the hippocampal volume, it nonetheless disrupted memory retention in a water maze in preoperatively trained rats. New learning in a different water maze was attenuated. No significant impairment occurred in rats with longitudinally oriented cuts, or in animals with ibotenic acid-induced lesions of similar magnitude. To characterize the effect of a focal lesion on the integrity of longitudinally projecting axons, we stained degenerating cells and fibers in rats with unilateral CA3 transections by using FluoroJade-B. Degenerating terminals were seen across a wide region posterior to the cut, and were present in the strata of areas CA3 and CA1 that are innervated by CA3 pyramidal cells. These results suggest that the integrity of longitudinally oriented, translamellar axons of CA3 pyramidal cells may be necessary for efficient acquisition and retention of spatial memory.

  18. Stress affects theta activity in limbic networks and impairs novelty-induced exploration and familiarization

    PubMed Central

    Jacinto, Luis R.; Reis, Joana S.; Dias, Nuno S.; Cerqueira, João J.; Correia, José H.; Sousa, Nuno

    2013-01-01

    Exposure to a novel environment triggers the response of several brain areas that regulate emotional behaviors. Here, we studied theta oscillations within the hippocampus (HPC)-amygdala (AMY)-medial prefrontal cortex (mPFC) network in exploration of a novel environment and subsequent familiarization through repeated exposures to that same environment; in addition, we assessed how concomitant stress exposure could disrupt this activity and impair both behavioral processes. Local field potentials (LFP) were simultaneously recorded from dorsal and ventral hippocampus (dHPC and vHPC, respectively), basolateral amygdala (BLA) and mPFC in freely behaving rats while they were exposed to a novel environment, then repeatedly re-exposed over the course of 3 weeks to that same environment and, finally, on re-exposure to a novel unfamiliar environment. A longitudinal analysis of theta activity within this circuit revealed a reduction of vHPC and BLA theta power and vHPC-BLA theta coherence through familiarization which was correlated with a return to normal exploratory behavior in control rats. In contrast, a persistent over-activation of the same brain regions was observed in stressed rats that displayed impairments in novel exploration and familiarization processes. Importantly, we show that stress also affected intra-hippocampal synchrony and heightened the coherence between vHPC and BLA. In summary, we demonstrate that modulatory theta activity in the aforementioned circuit, namely in the vHPC and BLA, is correlated with the expression of anxiety in novelty-induced exploration and familiarization in both normal and pathological conditions. PMID:24137113

  19. Blockade of the dorsal hippocampal dopamine D1 receptors inhibits the scopolamine-induced state-dependent learning in rats.

    PubMed

    Piri, M; Rostampour, M; Nasehi, M; Zarrindast, M R

    2013-11-12

    In the present study, we investigated the possible role of the dorsal hippocampal (CA1) dopamine D1 receptors on scopolamine-induced amnesia as well as scopolamine state-dependent memory in adult male Wistar rats. Animals were bilaterally implanted with chronic cannulae in the CA1 regions of the dorsal hippocampus, trained in a step-through type inhibitory avoidance task, and tested 24h after training for their step-through latency. Results indicated that pre-training or pre-test intra-CA1 administration of scopolamine (1.5 and 3 μg/rat) dose-dependently reduced the step-through latency, showing an amnestic response. The pre-training scopolamine-induced amnesia (3 μg/rat) was reversed by the pre-test administration of scopolamine, indicating a state-dependent effect. Similarly, the pre-test administration of dopamine D1 receptor agonist, 1-phenyl-7,8-dihydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SKF38393; 1, 2 and 4 μg/rat, intra-CA1), could significantly reverse the scopolamine-induced amnesia. Interestingly, administration of an ineffective dose of scopolamine (0.25 μg/rat, intra-CA1) before different doses of SKF38393, blocked the reversal effect of SKF38393 on the pre-training scopolamine-induced amnesia. Moreover, while the pre-test intra-CA1 injection of the dopamine D1 receptor antagonist, R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH23390; 0.1 and 0.5 μg/rat, intra-CA1), resulted in apparent memory impairment, microinjection of the same doses of this agent inhibited the scopolamine-induced state-dependent memory. These results indicate that the CA1 dopamine D1 receptors may potentially play an important role in scopolamine-induced amnesia as well as the scopolamine state-dependent memory. Furthermore, our results propose that dopamine D1 receptor agonist, SKF38393 reverses the scopolamine-induced amnesia via acetylcholine release and possibly through the activation of muscarinic

  20. Reversible short-term and delayed long-term cognitive impairment induced by chronic mild cerebral hypoperfusion in rats.

    PubMed

    Thong-asa, Khwanjai; Chompoopong, Supin; Tantisira, Mayuree H; Tilokskulchai, Kanokwan

    2013-08-01

    Chronic cerebral hypoperfusion induced by aging in combination with vascular disorder potentially contributes to the development of vascular dementia. This study aimed to investigate the age-related changes in spatial performances in chronic mild cerebral hypoperfusion induced by permanent right common carotid artery occlusion (rCCAO) in rats. Four-month-old male Sprague-Dawley rats (n = 20) were randomly assigned into sham and rCCAO groups. Spatial performances of young adult rats (age 4-8 months) were evaluated repeatedly by the radial arm water maze at 6 days, and 1, 2 and 4 months after surgery. The spatial performance was re-assessed by the Morris water maze when the rats were 18 months old. The present results revealed that the rCCAO rats developed progressive deficit in spatial learning and memory, starting from day 6 and significant deficit was found at 2 months after rCCAO (p < 0.05). However, the spatial performance of the rCCAO rats was recovered at 4 months after surgery. Testing of the cognitive flexibility of the aged rCCAO rats (18 months old), indicated that the learning flexibility of the aged rCCAO rats was significantly impaired. This deficit was found in parallel with pronounced white matter damage in the corpus callosum and internal capsule and significant cell death in the dorsal hippocampus. Our results suggested that vascular risk insult in young adult rats resulted in spatial learning deficit which could be completely compensated later on. However, such previous vascular risk could be exacerbated by advancing age and subsequently lead to a deficit in cognitive flexibility with white matter damage and significant neuronal death in the dorsal hippocampus.

  1. Region-specific response of the hippocampus to chronic unpredictable stress.

    PubMed

    Hawley, Darby F; Leasure, J Leigh

    2012-06-01

    The objective of the present study was to determine whether chronic unpredictable stress (CUS) would induce hippocampal neuroplasticity in a region-specific manner. Recent evidence suggests that the hippocampus has two functionally distinct subsections. The dorsal (septal) portion appears to be primarily associated with spatial navigation, while the ventral (temporal) region has been linked to affect-related functions, such as anxiety. Chronic stress has previously been shown to negatively affect the hippocampus by decreasing survival of progenitor cells, although it has also been shown to increase adaptive responses, such as increased expression of neuropeptide Y (NPY) and ΔFosB. Whether such events occur in a region-specific manner has not been investigated. We hypothesized that CUS would selectively impact cell survival, NPY, and ΔFosB expression in the more affect-related ventral subregion. Individually housed Long-Evans rats (n = 31) were divided into two groups: stressed and control. Stressed animals were exposed daily to an unpredictable schedule of ethologically relevant stressors, such as predator odors, forced swim, and open field exposure. All rats were injected with bromodeoxyuridine (BrdU) daily during the first 5 days of CUS in order to label dividing progenitor cells. Unbiased stereology was used to quantify BrdU+, NPY+, and ΔFosB+ cells in dorsal and ventral hippocampal subregions. In support of our hypothesis, we found that CUS selectively decreased cell survival in the ventral subregion. However, both NPY and ΔFosB were significantly increased only in the dorsal hippocampus. These results suggest that stress-induced adaptive neuroplasticity occurs primarily in the dorsal subregion, which may coincide with behavioral aspects of the stress response, such as avoidance or amelioration of the stressor.

  2. The Role of the Hippocampus in Retaining Relational Information across Short Delays: The Importance of Memory Load

    ERIC Educational Resources Information Center

    Jeneson, Annette; Mauldin, Kristin N.; Hopkins, Ramona O.; Squire, Larry R.

    2011-01-01

    Patients with hippocampal damage are sometimes impaired at remembering information across delays as short as a few seconds. How are these impairments to be understood? One possibility is that retention of some kinds of information is critically dependent on the hippocampus, regardless of the retention interval and regardless of whether the task…

  3. Interactions between the lateral habenula and the hippocampus: implication for spatial memory processes.

    PubMed

    Goutagny, Romain; Loureiro, Michael; Jackson, Jesse; Chaumont, Joseph; Williams, Sylvain; Isope, Philippe; Kelche, Christian; Cassel, Jean-Christophe; Lecourtier, Lucas

    2013-11-01

    The lateral habenula (LHb) is an epithalamic structure connected with both the basal ganglia and the limbic system and that exerts a major influence on midbrain monoaminergic nuclei. The current view is that LHb receives and processes cortical information in order to select proper strategies in a variety of behavior. Recent evidence indicates that LHb might also be implicated in hippocampus-dependent memory processes. However, if and how LHb functionally interacts with the dorsal hippocampus (dHPC) is still unknown. We therefore performed simultaneous recordings within LHb and dHPC in both anesthetized and freely moving rats. We first showed that a subset of LHb cells were phase-locked to hippocampal theta oscillations. Furthermore, LHb generated spontaneous theta oscillatory activity, which was highly coherent with hippocampal theta oscillations. Using reversible LHb inactivation, we found that LHb might regulate dHPC theta oscillations. In addition, we showed that LHb silencing altered performance in a hippocampus-dependent spatial recognition task. Finally, increased coherence between LHb and dHPC was positively correlated to the memory performance in this test. Collectively, these results suggest that LHb functionally interacts with the hippocampus and is involved in hippocampus-dependent spatial information processing.

  4. Visual Impairment

    MedlinePlus

    ... Loss Surgery? A Week of Healthy Breakfasts Shyness Visual Impairment KidsHealth > For Teens > Visual Impairment Print A ... with the brain, making vision impossible. What Is Visual Impairment? Many people have some type of visual ...

  5. Dissociated repetition deficits in aphasia can reflect flexible interactions between left dorsal and ventral streams and gender-dimorphic architecture of the right dorsal stream

    PubMed Central

    Berthier, Marcelo L.; Froudist Walsh, Seán; Dávila, Guadalupe; Nabrozidis, Alejandro; Juárez y Ruiz de Mier, Rocío; Gutiérrez, Antonio; De-Torres, Irene; Ruiz-Cruces, Rafael; Alfaro, Francisco; García-Casares, Natalia

    2013-01-01

    Assessment of brain-damaged subjects presenting with dissociated repetition deficits after selective injury to either the left dorsal or ventral auditory pathways can provide further insight on their respective roles in verbal repetition. We evaluated repetition performance and its neural correlates using multimodal imaging (anatomical MRI, DTI, fMRI, and18FDG-PET) in a female patient with transcortical motor aphasia (TCMA) and in a male patient with conduction aphasia (CA) who had small contiguous but non-overlapping left perisylvian infarctions. Repetition in the TCMA patient was fully preserved except for a mild impairment in nonwords and digits, whereas the CA patient had impaired repetition of nonwords, digits and word triplet lists. Sentence repetition was impaired, but he repeated novel sentences significantly better than clichés. The TCMA patient had tissue damage and reduced metabolism in the left sensorimotor cortex and insula. DTI showed damage to the left temporo-frontal and parieto-frontal segments of the arcuate fasciculus (AF) and part of the left ventral stream together with well-developed right dorsal and ventral streams, as has been reported in more than one-third of females. The CA patient had tissue damage and reduced metabolic activity in the left temporoparietal cortex with additional metabolic decrements in the left frontal lobe. DTI showed damage to the left temporo-parietal and temporo-frontal segments of the AF, but the ventral stream was spared. The direct segment of the AF in the right hemisphere was also absent with only vestigial remains of the other dorsal subcomponents present, as is often found in males. fMRI during word and nonword repetition revealed bilateral perisylvian activation in the TCMA patient suggesting recruitment of spared segments of the left dorsal stream and right dorsal stream with propagation of signals to temporal lobe structures suggesting a compensatory reallocation of resources via the ventral streams. The CA

  6. Dissociated repetition deficits in aphasia can reflect flexible interactions between left dorsal and ventral streams and gender-dimorphic architecture of the right dorsal stream.

    PubMed

    Berthier, Marcelo L; Froudist Walsh, Seán; Dávila, Guadalupe; Nabrozidis, Alejandro; Juárez Y Ruiz de Mier, Rocío; Gutiérrez, Antonio; De-Torres, Irene; Ruiz-Cruces, Rafael; Alfaro, Francisco; García-Casares, Natalia

    2013-01-01

    Assessment of brain-damaged subjects presenting with dissociated repetition deficits after selective injury to either the left dorsal or ventral auditory pathways can provide further insight on their respective roles in verbal repetition. We evaluated repetition performance and its neural correlates using multimodal imaging (anatomical MRI, DTI, fMRI, and(18)FDG-PET) in a female patient with transcortical motor aphasia (TCMA) and in a male patient with conduction aphasia (CA) who had small contiguous but non-overlapping left perisylvian infarctions. Repetition in the TCMA patient was fully preserved except for a mild impairment in nonwords and digits, whereas the CA patient had impaired repetition of nonwords, digits and word triplet lists. Sentence repetition was impaired, but he repeated novel sentences significantly better than clichés. The TCMA patient had tissue damage and reduced metabolism in the left sensorimotor cortex and insula. DTI showed damage to the left temporo-frontal and parieto-frontal segments of the arcuate fasciculus (AF) and part of the left ventral stream together with well-developed right dorsal and ventral streams, as has been reported in more than one-third of females. The CA patient had tissue damage and reduced metabolic activity in the left temporoparietal cortex with additional metabolic decrements in the left frontal lobe. DTI showed damage to the left temporo-parietal and temporo-frontal segments of the AF, but the ventral stream was spared. The direct segment of the AF in the right hemisphere was also absent with only vestigial remains of the other dorsal subcomponents present, as is often found in males. fMRI during word and nonword repetition revealed bilateral perisylvian activation in the TCMA patient suggesting recruitment of spared segments of the left dorsal stream and right dorsal stream with propagation of signals to temporal lobe structures suggesting a compensatory reallocation of resources via the ventral streams. The

  7. Neural Representations of Location Outside the Hippocampus

    ERIC Educational Resources Information Center

    Knierim, James J.

    2006-01-01

    Place cells of the rat hippocampus are a dominant model system for understanding the role of the hippocampus in learning and memory at the level of single-unit and neural ensemble responses. A complete understanding of the information processing and computations performed by the hippocampus requires detailed knowledge about the properties of the…

  8. Syntactic processing depends on dorsal language tracts.

    PubMed

    Wilson, Stephen M; Galantucci, Sebastiano; Tartaglia, Maria Carmela; Rising, Kindle; Patterson, Dianne K; Henry, Maya L; Ogar, Jennifer M; DeLeon, Jessica; Miller, Bruce L; Gorno-Tempini, Maria Luisa

    2011-10-20

    Frontal and temporal language areas involved in syntactic processing are connected by several dorsal and ventral tracts, but the functional roles of the different tracts are not well understood. To identify which white matter tract(s) are important for syntactic processing, we examined the relationship between white matter damage and syntactic deficits in patients with primary progressive aphasia, using multimodal neuroimaging and neurolinguistic assessment. Diffusion tensor imaging showed that microstructural damage to left hemisphere dorsal tracts--the superior longitudinal fasciculus including its arcuate component--was strongly associated with deficits in comprehension and production of syntax. Damage to these dorsal tracts predicted syntactic deficits after gray matter atrophy was taken into account, and fMRI confirmed that these tracts connect regions modulated by syntactic processing. In contrast, damage to ventral tracts--the extreme capsule fiber system or the uncinate fasciculus--was not associated with syntactic deficits. Our findings show that syntactic processing depends primarily on dorsal language tracts.

  9. Quantifying dorsal closure in three dimensions

    PubMed Central

    Lu, Heng; Sokolow, Adam; Kiehart, Daniel P.; Edwards, Glenn S.

    2016-01-01

    Dorsal closure is an essential stage of Drosophila embryogenesis and is a powerful model system for morphogenesis, wound healing, and tissue biomechanics. During closure, two flanks of lateral epidermis close an eye-shaped dorsal opening that is filled with amnioserosa. The two flanks of lateral epidermis are zipped together at each canthus (“corner” of the eye). Actomyosin-rich purse strings are localized at each of the two leading edges of lateral epidermis (“lids” of the eye). Here we report that each purse string indents the dorsal surface at each leading edge. The amnioserosa tissue bulges outward during the early-to-mid stages of closure to form a remarkably smooth, asymmetric dome indicative of an isotropic and uniform surface tension. Internal pressure of the embryo and tissue elastic properties help to shape the dorsal surface. PMID:27798232

  10. The bumps on the hippocampus

    NASA Astrophysics Data System (ADS)

    Gao, Yi; Ver Hoef, Lawrence

    2016-03-01

    The hippocampus has been the focus of more imaging research than any other subcortical structure in the human brain. However a feature that has been almost universally overlooked are the bumpy ridges on the inferior aspect of the hippocampus, which we refer to as hippocampal dentation. These bumps arise from folds in the CA1 layer of Ammon's horn. Similar to the folding of the cerebral cortex, hippocampal dentation allows for greater surface area in a confined space. However, while quantitative studies of radiologic brain images have been advancing for decades, examining numerous approaches to hippocampal segmentation and morphology analysis, virtually all published 3D renderings of the hippocampus show the under surface to be quite smooth or mildly irregular; we have rarely seen the characteristic bumpy structure in the reconstructed 3D scene, one exception being the 9.4T postmortem study. This is presumably due to the fact that, based on our experience with high resolution images, there is a dramatic degree of variability in hippocampal dentation between individuals from very smooth to highly dentated. An apparent question is, does this indicate that this specific morphological signature can only be captured using expensive ultra-high field techniques? Or, is such information buried in the data we commonly acquire, awaiting a computation technique that can extract and render it clearly? In this study, we propose a super-resolution technique that captures the fine scale morphometric features of the hippocampus based on common T1-weighted 3T MR images.

  11. Involvement of dorsal hippocampal and medial septal nicotinic receptors in cross state-dependent memory between WIN55, 212-2 and nicotine or ethanol in mice.

    PubMed

    Alijanpour, S; Rezayof, A

    2013-08-15

    The present study examined whether nicotinic acetylcholine receptors (nAChRs) of the CA1 regions of the dorsal hippocampus and medial septum (MS) are involved in cross state-dependent memory retrieval between WIN55, 212-2 (WIN, a non-selective CB1/CB2 receptor agonist) and nicotine or ethanol. Memory retrieval was measured in one-trial step-down type passive avoidance apparatus in male adult mice. Pre-training intraperitoneal administration of WIN (0.1-1mg/kg) dose-dependently impaired memory retrieval when it was tested 24h later. Pre-test systemic administration of nicotine (0.6 and 0.7mg/kg, s.c.) or ethanol (0.5g/kg, i.p.) improved WIN-induced memory impairment, suggesting a cross state-dependent memory retrieval between the drugs. Pre-test intra-CA1 microinjection of nicotine (1 and 2μg/mouse) before systemic administration of an ineffective dose of nicotine (0.5mg/kg, s.c.) or ethanol (0.25g/kg) significantly reversed WIN-induced memory impairment. Pre-test intra-CA1 microinjection of mecamylamine (1 and 3μg/mouse) inhibited cross state-dependent memory between WIN and nicotine or ethanol. Moreover, pre-test intra-MS microinjection of nicotine (1 and 2μg/mouse) in combination with systemic administration of a lower dose of nicotine (0.5mg/kg), but not ethanol (0.25g/kg), improved memory impairment induced by pre-training administration of WIN. On the other hand, in the animals that received pre-training WIN and pre-test systemic administration of nicotine (0.7mg/kg), but not ethanol (0.5g/kg), pre-test intra-MS microinjection of mecamylamine (1-5μg/mouse) inhibited WIN-nicotine state-dependent memory retrieval. It should be noted that pre-test intra-CA1 or intra-MS microinjection of nicotine or mecamylamine by itself had no effect on memory retrieval and also could not reverse memory impairment induced by pre-training administration of WIN. It can be concluded that WIN and nicotine or WIN and ethanol can induce state-dependent memory retrieval. In

  12. Personal authentication through dorsal hand vein patterns

    NASA Astrophysics Data System (ADS)

    Hsu, Chih-Bin; Hao, Shu-Sheng; Lee, Jen-Chun

    2011-08-01

    Biometric identification is an emerging technology that can solve security problems in our networked society. A reliable and robust personal verification approach using dorsal hand vein patterns is proposed in this paper. The characteristic of the approach needs less computational and memory requirements and has a higher recognition accuracy. In our work, the near-infrared charge-coupled device (CCD) camera is adopted as an input device for capturing dorsal hand vein images, it has the advantages of the low-cost and noncontact imaging. In the proposed approach, two finger-peaks are automatically selected as the datum points to define the region of interest (ROI) in the dorsal hand vein images. The modified two-directional two-dimensional principal component analysis, which performs an alternate two-dimensional PCA (2DPCA) in the column direction of images in the 2DPCA subspace, is proposed to exploit the correlation of vein features inside the ROI between images. The major advantage of the proposed method is that it requires fewer coefficients for efficient dorsal hand vein image representation and recognition. The experimental results on our large dorsal hand vein database show that the presented schema achieves promising performance (false reject rate: 0.97% and false acceptance rate: 0.05%) and is feasible for dorsal hand vein recognition.

  13. Identification of oxytocin receptor in the dorsal horn and nociceptive dorsal root ganglion neurons.

    PubMed

    Moreno-López, Y; Martínez-Lorenzana, G; Condés-Lara, M; Rojas-Piloni, G

    2013-04-01

    Oxytocin (OT) secreted by the hypothalamo-spinal projection exerts antinociceptive effects in the dorsal horn. Electrophysiological evidence indicates that OT could exert these effects by activating OT receptors (OTR) directly on dorsal horn neurons and/or primary nociceptive afferents in the dorsal root ganglia (DRG). However, little is known about the identity of the dorsal horn and DRG neurons that express the OTR. In the dorsal horn, we found that the OTR is expressed principally in neurons cell bodies. However, neither spino-thalamic dorsal horn neurons projecting to the contralateral thalamic ventral posterolateral nucleus (VPL) and posterior nuclear group (Po) nor GABaergic dorsal horn neurons express the OTR. The OTR is not expressed in skin nociceptive terminals or in dorsal horn nociceptive fibers. In the DRG, however, the OTR is expressed predominantly in non-peptidergic C-fiber cell bodies, but not in peptidergic or mechanoreceptor afferents or in skin nociceptive terminals. Our results suggest that the antinociceptive effects of OT are mediated by direct activation of dorsal horn neurons and peripheral actions on nociceptive, non-peptidergic C-afferents in the DRG.

  14. Cholinergic Modulation of the Hippocampus during Encoding and Retrieval of Tone/Shock-Induced Fear Conditioning

    ERIC Educational Resources Information Center

    Rogers, Jason L.; Kesner, Raymond P.

    2004-01-01

    We investigated the role of acetylcholine (ACh) during encoding and retrieval of tone/shock-induced fear conditioning with the aim of testing Hasselmo's cholinergic modulation model of encoding and retrieval using a task sensitive to hippocampal disruption. Lesions of the hippocampus impair acquisition and retention of contextual conditioning with…

  15. Differential Effects of Cannabinoid Receptor Agonist on Social Discrimination and Contextual Fear in Amygdala and Hippocampus

    ERIC Educational Resources Information Center

    Segev, Amir; Akirav, Irit

    2011-01-01

    We examined whether the cannabinoid receptor agonist WIN55,212-2 (WIN; 5 [mu]g/side) microinjected into the hippocampus or the amygdala would differentially affect memory processes in a neutral vs. an aversive task. In the aversive contextual fear task, WIN into the basolateral amygdala impaired fear acquisition/consolidation, but not retrieval.…

  16. Kindling-Induced Changes in Plasticity of the Rat Amygdala and Hippocampus

    ERIC Educational Resources Information Center

    Schubert, Manja; Siegmund, Herbert; Pape, Hans-Christian; Albrecht, Doris

    2005-01-01

    Temporal lobe epilepsy (TLE) is often accompanied by interictal behavioral abnormalities, such as fear and memory impairment. To identify possible underlying substrates, we analyzed long-term synaptic plasticity in two relevant brain regions, the lateral amygdala (LA) and the CA1 region of the hippocampus, in the kindling model of epilepsy. Wistar…

  17. Sleep deprivation reduces proliferation of cells in the dentate gyrus of the hippocampus in rats

    PubMed Central

    guzmán-marín, Ruben; Suntsova, Natalia; Stewart, Darya R; Gong, Hui; Szymusiak, Ronald; McGinty, Dennis

    2003-01-01

    The dentate gyrus (DG) of the adult hippocampus gives rise to progenitor cells, which have the potential to differentiate into neurons. To date it is not known whether sleep or sleep loss has any effect on proliferation of cells in the DG. Male rats were implanted for polysomnographic recording, and divided into treadmill sleep-deprived (SD), treadmill control (TC) and cage control (CC) groups. SD and TC rats were kept for 96 h on a treadmill that moved either for 3 s on/12 s off (SD group) or for 15 min on/60 min off (TC group) to equate total movement but permit sustained rest periods in TC animals. To label proliferating cells the thymidine analogue 5-bromo-2′-deoxyuridine (BrdU) was injected after the first 48 h of the experimental procedure in all groups (50 mg kg−1, i.p.). The percentage of time awake per day was 93.2 % in the SD group vs. 59.6 % in the TC group and 49.9 % in the CC group (P < 0.001). Stereological analysis showed that the number of BrdU-positive cells in the DG of the dorsal hippocampus was reduced by 54 % in the SD group in comparison with the TC and by 68 % in comparison with the CC group. These results suggest that sleep deprivation reduces proliferation of cells in the DG of the dorsal hippocampus. PMID:12679377

  18. β-amyloid disrupts human NREM slow waves and related hippocampus-dependent memory consolidation

    PubMed Central

    Mander, Bryce A.; Marks, Shawn M.; Vogel, Jacob W.; Rao, Vikram; Lu, Brandon; Saletin, Jared M.; Ancoli-Israel, Sonia; Jagust, William J.; Walker, Matthew P.

    2015-01-01

    Independent evidence associates β-amyloid pathology with both NREM sleep disruption and memory impairment in older adults. However, whether the influence of β-amyloid pathology on hippocampus-dependent memory is, in part, driven by impairments of NREM slow wave activity (SWA) and associated overnight memory consolidation is unknown. Here, we show that β-amyloid burden within medial prefrontal cortex (mPFC) is significantly correlated with the severity of impairment in NREM SWA generation. Moreover, reduced NREM SWA generation was further associated with impaired overnight memory consolidation and impoverished hippocampal-neocortical memory transformation. Furthermore, structural equation models revealed that the association between mPFC β-amyloid pathology and impaired hippocampus-dependent memory consolidation is not direct, but instead, statistically depends on the intermediary factor of diminished NREM SWA. By linking β-amyloid pathology with impaired NREM SWA, these data implicate sleep disruption as a novel mechanistic pathway through which β-amyloid pathology may contribute to hippocampus-dependent cognitive decline in the elderly. PMID:26030850

  19. Conscious Experience and Episodic Memory: Hippocampus at the Crossroads

    PubMed Central

    Behrendt, Ralf-Peter

    2013-01-01

    If an instance of conscious experience of the seemingly objective world around us could be regarded as a newly formed event memory, much as an instance of mental imagery has the content of a retrieved event memory, and if, therefore, the stream of conscious experience could be seen as evidence for ongoing formation of event memories that are linked into episodic memory sequences, then unitary conscious experience could be defined as a symbolic representation of the pattern of hippocampal neuronal firing that encodes an event memory – a theoretical stance that may shed light into the mind-body and binding problems in consciousness research. Exceedingly detailed symbols that describe patterns of activity rapidly self-organizing, at each cycle of the θ rhythm, in the hippocampus are instances of unitary conscious experience that jointly constitute the stream of consciousness. Integrating object information (derived from the ventral visual stream and orbitofrontal cortex) with contextual emotional information (from the anterior insula) and spatial environmental information (from the dorsal visual stream), the hippocampus rapidly forms event codes that have the informational content of objects embedded in an emotional and spatiotemporally extending context. Event codes, formed in the CA3-dentate network for the purpose of their memorization, are not only contextualized but also allocentric representations, similarly to conscious experiences of events and objects situated in a seemingly objective and observer-independent framework of phenomenal space and time. Conscious perception, creating the spatially and temporally extending world that we perceive around us, is likely to be evolutionarily related to more fleeting and seemingly internal forms of conscious experience, such as autobiographical memory recall, mental imagery, including goal anticipation, and to other forms of externalized conscious experience, namely dreaming and hallucinations; and evidence pointing

  20. Conscious experience and episodic memory: hippocampus at the crossroads.

    PubMed

    Behrendt, Ralf-Peter

    2013-01-01

    If an instance of conscious experience of the seemingly objective world around us could be regarded as a newly formed event memory, much as an instance of mental imagery has the content of a retrieved event memory, and if, therefore, the stream of conscious experience could be seen as evidence for ongoing formation of event memories that are linked into episodic memory sequences, then unitary conscious experience could be defined as a symbolic representation of the pattern of hippocampal neuronal firing that encodes an event memory - a theoretical stance that may shed light into the mind-body and binding problems in consciousness research. Exceedingly detailed symbols that describe patterns of activity rapidly self-organizing, at each cycle of the θ rhythm, in the hippocampus are instances of unitary conscious experience that jointly constitute the stream of consciousness. Integrating object information (derived from the ventral visual stream and orbitofrontal cortex) with contextual emotional information (from the anterior insula) and spatial environmental information (from the dorsal visual stream), the hippocampus rapidly forms event codes that have the informational content of objects embedded in an emotional and spatiotemporally extending context. Event codes, formed in the CA3-dentate network for the purpose of their memorization, are not only contextualized but also allocentric representations, similarly to conscious experiences of events and objects situated in a seemingly objective and observer-independent framework of phenomenal space and time. Conscious perception, creating the spatially and temporally extending world that we perceive around us, is likely to be evolutionarily related to more fleeting and seemingly internal forms of conscious experience, such as autobiographical memory recall, mental imagery, including goal anticipation, and to other forms of externalized conscious experience, namely dreaming and hallucinations; and evidence pointing to

  1. A grasp-related deficit in tactile discrimination following dorsal column lesion in the rat.

    PubMed

    Ballermann, M; McKenna, J; Whishaw, I Q

    2001-01-15

    The dorsal columns of the spinal cord are a major source of haptic (sense of active touch) and proprioceptive input to the brainstem and sensory-motor cortex. Following injury in primates, there are impairments in two-point discrimination, direction of movement across the skin, and frequency of vibration, and qualitative control of the digits, but simple spatial discriminations recover. In the rat there are qualitative deficits in paw control in skilled reaching, but no sensory deficits have been reported. Because recent investigations of sensory control suggest that sensory functions may be related to specific actions, the present study investigated whether the dorsal columns contribute to hapsis during food grasping in the rat. Adult female Long-Evans rats were trained to reach with a single forepaw for a piece of uncooked pasta or for equivalent sized but tactually different nonfood items. One group was given lesions of the dorsal column ipsilateral to their preferred paw, while the second group served as a control. Postlesion, both groups were tested for skilled reaching success and force application as well as adhesive dot removal and forepaw placing. Performance levels on these tests were normal. Nevertheless, the rats with dorsal column lesions were unable to discriminate a food item from a tactually distinctive nonfood item as part of the reaching act, suggesting that the dorsal columns are important for on-line tactile discriminations, or "haptic actions," which contribute to the normal performance of grasping actions.

  2. Influence of prenatal noise and music on the spatial memory and neurogenesis in the hippocampus of developing rats.

    PubMed

    Kim, Hong; Lee, Myoung-Hwa; Chang, Hyun-Kyung; Lee, Taeck-Hyun; Lee, Hee-Hyuk; Shin, Min-Chul; Shin, Mal-Soon; Won, Ran; Shin, Hye-Sook; Kim, Chang-Ju

    2006-03-01

    During the prenatal period, the development of individual is influenced by the environmental factors. In the present study, the influence of prenatal noise and music on the spatial memory and neurogenesis in the hippocampus of developing rats was investigated. The exposure to the noise during pregnancy caused growth retardation, decreased neurogenesis in the hippocampus, and impaired spatial learning ability in pups. The exposure to music during pregnancy, on the other hand, caused increased neurogenesis in the hippocampus and enhanced spatial learning ability in pups. The present study has shown the importance of the prenatal environmental conditions for the cognition and brain development.

  3. Region-specific upregulation of parvalbumin-, but not calretinin-positive cells in the ventral hippocampus during adolescence.

    PubMed

    Caballero, Adriana; Diah, Kimberly C; Tseng, Kuei Y

    2013-12-01

    Animal studies have highlighted the role of the ventral hippocampus-prefrontal cortex pathway in the acquisition of mature cortical function through refinement of GABAergic circuits during adolescence. Inhibitory GABAergic responses are mediated by highly specialized interneurons, which have distinct functional properties and are characterized by the expression of calcium binding proteins. Among these, we recently found that parvalbumin (PV)- and calretinin (CR)-positive interneurons in the prefrontal cortex follow opposite developmental trajectories during the periadolescent transition period. In the present study, we asked whether interneurons expressing PV and CR in the ventral hippocampus follow similar periadolescent trajectories as seen in the prefrontal cortex. By measuring the relative abundance of these interneurons in three age groups (postnatal days (PD) 25-40, 45-55, and 60-85), we found that regions within the dorso-ventral axis of the ventral hippocampus undergo distinct developmental trajectories in PV expression during the periadolescent transition. Specifically, the ventral subiculum displayed a dramatic increase in PV-positive interneurons from PD25-40 to PD45-55 with an increasing rostro-caudal gradient, whereas negligible changes were found in the dorsal and middle regions. In contrast, the number of CR-positive interneurons in the ventral hippocampus remained unchanged across the three age groups studied. Together, these results describe for the first time that GABAergic circuits in the ventral hippocampus undergo protracted development during adolescence, in particular the PV-positive cell population circumscribed to the ventral region of the ventral hippocampus.