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Sample records for limbic forebrain noradrenergic

  1. Ropinirole regulates emotionality and neuronal activity markers in the limbic forebrain.

    PubMed

    Mavrikaki, Maria; Schintu, Nicoletta; Nomikos, George G; Panagis, George; Svenningsson, Per

    2014-12-01

    Restless legs syndrome (RLS) and Parkinson's disease (PD) are movement disorders usually accompanied by emotional and cognitive deficits. Although D3/D2 receptor agonists are effective against motor and non-motor deficits in RLS and PD, the exact behavioral and neurochemical effects of these drugs are not clearly defined. This study aimed to evaluate the effects of acute ropinirole (0, 0.1, 1 or 10 mg/kg, i.p.), a preferential D3/D2 receptor agonist, on intracranial self-stimulation (ICSS), spontaneous motor activity, anxiety- and depression-like behaviors, spatial reference and working memory in rats as well as on certain markers of neuronal activity, i.e. induction of immediate early genes, such as c-fos and arc, and crucial phosphorylations on GluA1 subunit of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and NA1, NA2A and NA2B subunits of N-methyl-D-aspartate (NMDA) receptors. Ropinirole decreased ICSS thresholds and induced anxiolytic- and antidepressive-like effects without affecting motor activity or spatial memory. The effects on emotionality were associated with a decrease in p-Ser897-NA1 and an increase in p-Tyr1472-NA2B in the ventral striatum as well as an increased induction of c-fos messenger RNA (mRNA) in the prefrontal cortex (PFC) and decreased expression of arc mRNA in the striatum and the shell of the nucleus accumbens. Our data indicate that ropinirole significantly affects emotionality at doses (1-10 mg/kg, i.p.) that exert no robust effects on locomotion or cognition. The data reinforce the use of D3/D2 receptor agonists in the treatment of RLS and PD patients characterized by emotional deficits and suggest that altered NMDA-mediated neurotransmission in the limbic forebrain may underlie some of ropinirole's therapeutic actions. PMID:24852388

  2. SVZ-derived newly generated neurons populate several olfactory and limbic forebrain regions

    PubMed Central

    Shapiro, Lee A.; Ng, Kwan; Zhou, Qun-Yong; Ribak, Charles E.

    2009-01-01

    Neurogenesis persists in several regions of the adult mammalian brain. Although the hippocampus and olfactory bulb are most commonly studied in the context of adult neurogenesis, there is an increasing body of evidence in support of neurogenesis occurring outside of these two regions. The current study expands upon previous data by showing newborn neurons with a mature phenotype are located in several olfactory and limbic structures outside of the hippocampus and olfactory bulb, where we previously described DCX/BrdU immature neurons. Notably, newborn neurons with a mature neuronal phenotype are found in the olfactory tubercles, anterior olfactory nuclei, tenia tecta, islands of Calleja, amygdala and lateral entorhinal cortex. The appearance of newborn neurons with a mature phenotype in these regions suggests that these structures are destinations, and that newborn neurons are not simply passing through these structures. In light of the increasing body of evidence for neurogenesis in these, and other olfactory, limbic and striatal structures, we hypothesize that brain regions displaying adult neurogenesis are functionally linked. PMID:18849007

  3. Limbic encephalitis

    PubMed Central

    Mahawish, Karim; Teinert, Lynne; Cavanagh, Kathryn; Brennan, Joseph

    2014-01-01

    We present a case of paraneoplastic limbic encephalitis, describing the presenting features, diagnosis and management plan. Limbic encephalitis is one differential of rapidly progressive dementia. We describe a rational approach to the diagnosis of the patient with rapid cognitive decline. PMID:24891487

  4. Noradrenergic Modulation of Arousal

    PubMed Central

    Berridge, Craig W.

    2008-01-01

    Through a highly divergent efferent projection system, the locus coeruleus-noradrenergic system supplies norepinephrine throughout the central nervous system. State-dependent neuronal discharge activity of locus coeruleus neurons has long-suggested a role of this system in the induction of an alert waking state. More recent work supports this hypothesis, demonstrating robust wake-promoting actions of the locus coeruleus-noradrenergic system. Norepinephrine enhances arousal, in part, via actions of β- and α1-receptors located within multiple subcortical structures, including the general regions of the medial septal area and the medial preoptic areas. Recent anatomical studies suggest that arousal-enhancing actions of norepinephrine are not limited to the locus coeruleus system and likely include the A1 and A2 noradrenergic cell groups. Thus, noradrenergic modulation of arousal state involves multiple noradrenergic systems acting with multiple subcortical regions. Pharmacological studies indicate that the combined actions of these systems are necessary for the sustained maintenance of arousal levels associated with spontaneous waking. Enhanced arousal state is a prominent aspect of both stress and psychostimulant drug action and evidence indicates that noradrenergic systems likely play an important role in both stress-related and psychostimulant-induced arousal. These and other observations suggest that the dysregulation of noradrenergic neurotransmission could well contribute to the dysregulation of arousal associated with a variety of behavioral disorders including insomnia and stress-related disorders. PMID:18199483

  5. Noradrenergic dysfunction in Alzheimer's disease

    PubMed Central

    Gannon, Mary; Che, Pulin; Chen, Yunjia; Jiao, Kai; Roberson, Erik D.; Wang, Qin

    2015-01-01

    The brain noradrenergic system supplies the neurotransmitter norepinephrine throughout the brain via widespread efferent projections, and plays a pivotal role in modulating cognitive activities in the cortex. Profound noradrenergic degeneration in Alzheimer's disease (AD) patients has been observed for decades, with recent research suggesting that the locus coeruleus (where noradrenergic neurons are mainly located) is a predominant site where AD-related pathology begins. Mounting evidence indicates that the loss of noradrenergic innervation greatly exacerbates AD pathogenesis and progression, although the precise roles of noradrenergic components in AD pathogenesis remain unclear. The aim of this review is to summarize current findings on noradrenergic dysfunction in AD, as well as to point out deficiencies in our knowledge where more research is needed. PMID:26136654

  6. Bilateral limbic system destruction in man

    PubMed Central

    Feinstein, Justin S.; Rudrauf, David; Khalsa, Sahib S.; Cassell, Martin D.; Bruss, Joel; Grabowski, Thomas J.; Tranel, Daniel

    2010-01-01

    We report here a case study of a rare neurological patient with bilateral brain damage encompassing a substantial portion of the so-called “limbic system.” The patient, Roger, has been studied in our laboratory for over 14 years and the current article presents his complete neuroanatomical and neuropsychological profiles. The brain damage occurred in 1980 following an episode of herpes simplex encephalitis. The amount of destroyed neural tissue is extensive and includes bilateral damage to core limbic and paralimbic regions, including the hippocampus, amygdala, parahippocampal gyrus, temporal poles, orbitofrontal cortex, basal forebrain, anterior cingulate cortex, and insular cortex. The right hemisphere is more extensively affected than the left, although the lesions are largely bilateral. Despite the magnitude of his brain damage, Roger has a normal IQ, average to above average attention, working memory, and executive functioning skills, and very good speech and language abilities. In fact, his only obvious presenting deficits are a dense global amnesia and a severe anosmia and ageusia. Roger's case presents a rare opportunity to advance our understanding of the critical functions underlying the human limbic system, and the neuropsychological and neuroanatomical data presented here provide a critical foundation for such investigations. PMID:19763994

  7. Dopaminergic, serotonergic, and noradrenergic deficits in Parkinson disease

    PubMed Central

    Buddhala, Chandana; Loftin, Susan K; Kuley, Brandon M; Cairns, Nigel J; Campbell, Meghan C; Perlmutter, Joel S; Kotzbauer, Paul T

    2015-01-01

    Objective People with Parkinson disease (PD) frequently develop dementia, which is associated with neocortical deposition of alpha-synuclein (α-syn) in Lewy bodies and Lewy neurites. In addition, neuronal loss and deposition of aggregated α-syn also occur in multiple subcortical nuclei that project to neocortical, limbic, and basal ganglia regions. Therefore, we quantified regional deficits in innervation from these PD-affected subcortical nuclei, by measuring the neurotransmitters and neurotransmitter transporter proteins originating from projections of dopaminergic neurons in substantia nigra pars compacta, serotonergic neurons in dorsal raphé nuclei, noradrenergic neurons in locus coeruleus, and cholinergic neurons in nucleus basalis of Meynert. Methods High-performance liquid chromatography and novel enzyme-linked immunosorbent assays were performed to quantify dopaminergic, serotonergic, noradrenergic, and cholinergic innervation in postmortem brain tissue. Eight brain regions from 15 PD participants (with dementia and Braak stage 6 α-syn deposition) and six age-matched controls were tested. Results PD participants compared to controls had widespread reductions of dopamine transporter in caudate, amygdala, hippocampus, inferior parietal lobule (IPL), precuneus, and visual association cortex (VAC) that exceeded loss of dopamine, which was only significantly reduced in caudate and amygdala. In contrast, PD participants had comparable deficits of both serotonin and serotonin transporter in caudate, middle frontal gyrus, IPL, and VAC. PD participants also had significantly reduced norepinephrine levels for all eight brain regions tested. Vesicular acetylcholine transporter levels were only quantifiable in caudate and hippocampus and did not differ between PD and control groups. Interpretation These results demonstrate widespread deficits in dopaminergic, serotonergic, and noradrenergic innervation of neocortical, limbic, and basal ganglia regions in advanced

  8. Limbic system (image)

    MedlinePlus

    ... structures which govern emotions and behavior. The limbic system, and in particular the hippocampus and amygdala, is involved in the formation of long-term memory, and is closely associated with the olfactory structures ( ...

  9. Forebrain-independent generation of hyperthermic convulsions in infant rats.

    PubMed

    Pospelov, Alexey S; Yukin, Alexey Y; Blumberg, Mark S; Puskarjov, Martin; Kaila, Kai

    2016-01-01

    Febrile seizures are the most common type of convulsive events in children. It is generally assumed that the generalization of these seizures is a result of brainstem invasion by the initial limbic seizure activity. Using precollicular transection in 13-day-old rats to isolate the forebrain from the brainstem, we demonstrate that the forebrain is not required for generation of tonic-clonic convulsions induced by hyperthermia or kainate. Compared with sham-operated littermate controls, latency to onset of convulsions in both models was significantly shorter in pups that had undergone precollicular transection, indicating suppression of the brainstem seizure network by the forebrain in the intact animal. We have shown previously that febrile seizures are precipitated by hyperthermia-induced respiratory alkalosis. Here, we show that triggering of hyperthermia-induced hyperventilation and consequent convulsions in transected animals are blocked by diazepam. The present data suggest that the role of endogenous brainstem activity in triggering tonic-clonic seizures should be re-evaluated in standard experimental models of limbic seizures. Our work sheds new light on the mechanisms that generate febrile seizures in children and, therefore, on how they might be treated. PMID:26547277

  10. Methylphenidate and Atomoxetine Inhibit Social Play Behavior through Prefrontal and Subcortical Limbic Mechanisms in Rats

    PubMed Central

    Achterberg, E.J. Marijke; van Kerkhof, Linda W.M.; Damsteegt, Ruth; Trezza, Viviana

    2015-01-01

    Positive social interactions during the juvenile and adolescent phases of life, in the form of social play behavior, are important for social and cognitive development. However, the neural mechanisms of social play behavior remain incompletely understood. We have previously shown that methylphenidate and atomoxetine, drugs widely used for the treatment of attention-deficit hyperactivity disorder (ADHD), suppress social play in rats through a noradrenergic mechanism of action. Here, we aimed to identify the neural substrates of the play-suppressant effects of these drugs. Methylphenidate is thought to exert its effects on cognition and emotion through limbic corticostriatal systems. Therefore, methylphenidate was infused into prefrontal and orbitofrontal cortical regions as well as into several subcortical limbic areas implicated in social play. Infusion of methylphenidate into the anterior cingulate cortex, infralimbic cortex, basolateral amygdala, and habenula inhibited social play, but not social exploratory behavior or locomotor activity. Consistent with a noradrenergic mechanism of action of methylphenidate, infusion of the noradrenaline reuptake inhibitor atomoxetine into these same regions also reduced social play. Methylphenidate administration into the prelimbic, medial/ventral orbitofrontal, and ventrolateral orbitofrontal cortex, mediodorsal thalamus, or nucleus accumbens shell was ineffective. Our data show that the inhibitory effects of methylphenidate and atomoxetine on social play are mediated through a distributed network of prefrontal and limbic subcortical regions implicated in cognitive control and emotional processes. These findings increase our understanding of the neural underpinnings of this developmentally important social behavior, as well as the mechanism of action of two widely used treatments for ADHD. PMID:25568111

  11. Methylphenidate and atomoxetine inhibit social play behavior through prefrontal and subcortical limbic mechanisms in rats.

    PubMed

    Achterberg, E J Marijke; van Kerkhof, Linda W M; Damsteegt, Ruth; Trezza, Viviana; Vanderschuren, Louk J M J

    2015-01-01

    Positive social interactions during the juvenile and adolescent phases of life, in the form of social play behavior, are important for social and cognitive development. However, the neural mechanisms of social play behavior remain incompletely understood. We have previously shown that methylphenidate and atomoxetine, drugs widely used for the treatment of attention-deficit hyperactivity disorder (ADHD), suppress social play in rats through a noradrenergic mechanism of action. Here, we aimed to identify the neural substrates of the play-suppressant effects of these drugs. Methylphenidate is thought to exert its effects on cognition and emotion through limbic corticostriatal systems. Therefore, methylphenidate was infused into prefrontal and orbitofrontal cortical regions as well as into several subcortical limbic areas implicated in social play. Infusion of methylphenidate into the anterior cingulate cortex, infralimbic cortex, basolateral amygdala, and habenula inhibited social play, but not social exploratory behavior or locomotor activity. Consistent with a noradrenergic mechanism of action of methylphenidate, infusion of the noradrenaline reuptake inhibitor atomoxetine into these same regions also reduced social play. Methylphenidate administration into the prelimbic, medial/ventral orbitofrontal, and ventrolateral orbitofrontal cortex, mediodorsal thalamus, or nucleus accumbens shell was ineffective. Our data show that the inhibitory effects of methylphenidate and atomoxetine on social play are mediated through a distributed network of prefrontal and limbic subcortical regions implicated in cognitive control and emotional processes. These findings increase our understanding of the neural underpinnings of this developmentally important social behavior, as well as the mechanism of action of two widely used treatments for ADHD. PMID:25568111

  12. Forebrain Mechanisms of Nociception and Pain: Analysis through Imaging

    NASA Astrophysics Data System (ADS)

    Casey, Kenneth L.

    1999-07-01

    Pain is a unified experience composed of interacting discriminative, affective-motivational, and cognitive components, each of which is mediated and modulated through forebrain mechanisms acting at spinal, brainstem, and cerebral levels. The size of the human forebrain in relation to the spinal cord gives anatomical emphasis to forebrain control over nociceptive processing. Human forebrain pathology can cause pain without the activation of nociceptors. Functional imaging of the normal human brain with positron emission tomography (PET) shows synaptically induced increases in regional cerebral blood flow (rCBF) in several regions specifically during pain. We have examined the variables of gender, type of noxious stimulus, and the origin of nociceptive input as potential determinants of the pattern and intensity of rCBF responses. The structures most consistently activated across genders and during contact heat pain, cold pain, cutaneous laser pain or intramuscular pain were the contralateral insula and anterior cingulate cortex, the bilateral thalamus and premotor cortex, and the cerebellar vermis. These regions are commonly activated in PET studies of pain conducted by other investigators, and the intensity of the brain rCBF response correlates parametrically with perceived pain intensity. To complement the human studies, we developed an animal model for investigating stimulus-induced rCBF responses in the rat. In accord with behavioral measures and the results of human PET, there is a progressive and selective activation of somatosensory and limbic system structures in the brain and brainstem following the subcutaneous injection of formalin. The animal model and human PET studies should be mutually reinforcing and thus facilitate progress in understanding forebrain mechanisms of normal and pathological pain.

  13. Noradrenergic Nuclei that Receive Sensory Input During Mating and Project to the Ventromedial Hypothalamus Play a Role in Mating-Induced Pseudopregnancy in the Female Rat

    PubMed Central

    Northrop, L. E.; Polston, E. K.; Erskine, M. S.

    2011-01-01

    In female rats, vaginal-cervical stimulation (VCS) received during mating induces bicircadian prolactin surges that are required for the maintenance of pregnancy or pseudopregnancy (PSP). The neural circuits that transmit VCS inputs to the brain have not been fully described, although mating stimulation is known to activate medullary noradrenergic cell groups that project to the forebrain. In response to VCS, these neurones release noradrenaline within the ventrolateral division of the ventromedial hypothalamus (VMHvl) and the posterodorsal medial amygdala (MePD), two forebrain sites that are implicated in the initiation of PSP. Noradrenaline receptor activation within the VMHvl is both necessary and sufficient for PSP induction, suggesting that noradrenaline acting within the VMHvl is particularly important in mediating the effects of VCS towards the establishment of PSP. We therefore investigated whether or not endogenous, VCS-induced noradrenaline release within the VMHvl is involved in PSP induction in the rat. Before the receipt of sufficient mating stimulation to induce PSP, a retrograde neurotoxin, dopamine-β-hydroxylase-saporin (DBH-SAP), was infused bilaterally into the either the VMHvl or the MePD to selectively destroy afferent noradrenergic nuclei in the brainstem. DBH-SAP infusions into the VMHvl lesioned mating-responsive noradrenergic neurones in A1 and A2 medullary nuclei and reduced the incidence of PSP by 50%. Infusions of DBH-SAP into the MePD had no effect on the subsequent induction of PSP. These results suggest that VCS is conveyed to mating-responsive forebrain areas by brainstem noradrenergic neurones, and that the activity of noradrenergic cells projecting to the VMHvl is involved in the induction of PSP. PMID:20673300

  14. Heritability of the limbic networks

    PubMed Central

    Kawadler, Jamie M.; Dell'Acqua, Flavio; Rijsdijk, Frühling V.; Kane, Fergus; Picchioni, Marco; McGuire, Philip; Toulopoulou, Timothea; Georgiades, Anna; Kalidindi, Sridevi; Kravariti, Eugenia; Murray, Robin M.; Murphy, Declan G.; Craig, Michael C.; Catani, Marco

    2016-01-01

    Individual differences in cognitive ability and social behaviour are influenced by the variability in the structure and function of the limbic system. A strong heritability of the limbic cortex has been previously reported, but little is known about how genetic factors influence specific limbic networks. We used diffusion tensor imaging tractography to investigate heritability of different limbic tracts in 52 monozygotic and 34 dizygotic healthy adult twins. We explored the connections that contribute to the activity of three distinct functional limbic networks, namely the dorsal cingulum (‘medial default-mode network’), the ventral cingulum and the fornix (‘hippocampal-diencephalic-retrosplenial network’) and the uncinate fasciculus (‘temporo-amygdala-orbitofrontal network’). Genetic and environmental variances were mapped for multiple tract-specific measures that reflect different aspects of the underlying anatomy. We report the highest heritability for the uncinate fasciculus, a tract that underpins emotion processing, semantic cognition, and social behaviour. High to moderate genetic and shared environmental effects were found for pathways important for social behaviour and memory, for example, fornix, dorsal and ventral cingulum. These findings indicate that within the limbic system inheritance of specific traits may rely on the anatomy of distinct networks and is higher for fronto-temporal pathways dedicated to complex social behaviour and emotional processing. PMID:26714573

  15. Heritability of the limbic networks.

    PubMed

    Budisavljevic, Sanja; Kawadler, Jamie M; Dell'Acqua, Flavio; Rijsdijk, Frühling V; Kane, Fergus; Picchioni, Marco; McGuire, Philip; Toulopoulou, Timothea; Georgiades, Anna; Kalidindi, Sridevi; Kravariti, Eugenia; Murray, Robin M; Murphy, Declan G; Craig, Michael C; Catani, Marco

    2016-05-01

    Individual differences in cognitive ability and social behaviour are influenced by the variability in the structure and function of the limbic system. A strong heritability of the limbic cortex has been previously reported, but little is known about how genetic factors influence specific limbic networks. We used diffusion tensor imaging tractography to investigate heritability of different limbic tracts in 52 monozygotic and 34 dizygotic healthy adult twins. We explored the connections that contribute to the activity of three distinct functional limbic networks, namely the dorsal cingulum ('medial default-mode network'), the ventral cingulum and the fornix ('hippocampal-diencephalic-retrosplenial network') and the uncinate fasciculus ('temporo-amygdala-orbitofrontal network'). Genetic and environmental variances were mapped for multiple tract-specific measures that reflect different aspects of the underlying anatomy. We report the highest heritability for the uncinate fasciculus, a tract that underpins emotion processing, semantic cognition, and social behaviour. High to moderate genetic and shared environmental effects were found for pathways important for social behaviour and memory, for example, fornix, dorsal and ventral cingulum. These findings indicate that within the limbic system inheritance of specific traits may rely on the anatomy of distinct networks and is higher for fronto-temporal pathways dedicated to complex social behaviour and emotional processing. PMID:26714573

  16. Evidence for a specialized role of the locus coeruleus noradrenergic system in cortical circuitries and behavioral operations.

    PubMed

    Chandler, Daniel J

    2016-06-15

    The brainstem nucleus locus coeruleus (LC) innervates the entire central nervous system and is the primary source of norepinephrine (NE) to the neocortex. While classically considered a homogenous modulator of forebrain activity by virtue of highly widespread and divergent axons, recent behavioral and pharmacological evidence suggest this nucleus may execute distinct operations within functionally distinct terminal fields. Summarized in this review are the anatomical and physiological properties of the nucleus within a historical context that led to the interpretation of the nucleus as a homogeneous entity with uniform and simultaneous actions throughout its terminal fields. Also included are findings from several laboratories which point to a more nuanced model of LC/NE function that parallels that seen in other forebrain-projecting monoaminergic nuclei. Such compartmentalized models of the nucleus promote the idea that specific LC circuits are involved in discrete behavioral operations, and therefore, by identifying the networks that are engaged by LC, the substrates for these behaviors can be identified and manipulated. Perturbations in the functional anatomy and physiology of this system may be related to neuropsychiatric conditions associated with dysregulation of the LC-noradrenergic system such as attention deficit hyperactivity disorder. Recent findings regarding the organization and operation of the LC/NE system collectively challenge the classical view of the nucleus as a relatively homogenous modulator of forebrain activity and provide the basis for a renewed scientific interest in this region of the brain. This article is part of a Special Issue entitled SI: Noradrenergic System. PMID:26607255

  17. Psychosurgery and the limbic system

    PubMed Central

    Kelly, Desmond

    1973-01-01

    The limbic system can be considered to consist of a central ‘core’ from which three well-defined circuits emerge. These are the Papez or medial circuit, the basolateral circuit and the defence reaction circuit. The functions of the primitive limbic brain are modulated by a higher order control—the frontal lobe. Emotional responses and physiological changes have been obtained by stimulation of fronto-limbic pathways and limbic circuits and these have been used for location of target sites in psychosurgery. For the relief of intractable depression and anxiety, lesions are generally made in the lower medial quadrant or posteroorbital part of the frontal lobe, where there is a concentration of fronto-limbic connections. In primary obsessional neurosis lesions at this site produce less satisfactory results, but these illnesses may be helped by lesions in the cingulate gyrus, which is part of the Papez circuit. Patients with epilepsy and aggressive outbursts may respond to temporal lobotomy, or to operations, such as amygdalotomy, where lesions are placed in the defence reaction circuit. PMID:4618902

  18. Direct targeting of peptidergic amygdalar neurons by noradrenergic afferents: linking stress-integrative circuitry

    PubMed Central

    Kravets, J. L.; Reyes, B. A. S.; Unterwald, E. M.; Van Bockstaele, E. J.

    2014-01-01

    Amygdalar norepinephrine (NE) plays a key role in regulating neural responses to emotionally arousing stimuli and is involved in memory consolidation of emotionally charged events. Corticotropin-releasing factor (CRF) and dynorphin (DYN), two neuropeptides that mediate the physiological and behavioral responses to stress, are abundant in the central nucleus of the amygdala (CeA), and directly innervate brainstem noradrenergic locus coeruleus (LC) neurons. Whether the CRF- and DYN-containing amygdalar neurons receive direct noradrenergic innervation has not yet been elucidated. The present study sought to define cellular substrates underlying noradrenergic modulation of CRF- and DYN-containing neurons in the CeA using immunohistochemistry and electron microscopy. Ultrastructural analysis revealed that NE-labeled axon terminals form synapses with CRF- and DYN-containing neurons in the CeA. Semi-quantitative analysis showed that approximately 31% of NET-labeled axon terminals targeted CeA neurons that co-expressed DYN and CRF. As a major source of CRF innervation to the LC, it is also not known whether CRF-containing CeA neurons are directly targeted by noradrenergic afferents. To test this, retrograde tract-tracing using FluoroGold (FG) from the LC was combined with immunocytochemical detection of CRF and NET in the CeA. Our results revealed a population of LC-projecting CRF-containing CeA neurons that are directly innervated by NE afferents. Analysis showed that approximately 34% of NET-labeled axon terminals targeted LC-projecting CeA neurons that contain CRF. Taken together, these results indicate significant interactions between NE, CRF, and DYN in this critical limbic region and reveal direct synaptic interactions of NE with amygdalar CRF that influence the LC-NE arousal system. PMID:24271021

  19. Thinking of attachments reduces noradrenergic stress response.

    PubMed

    Bryant, Richard A; Chan, Lilian

    2015-10-01

    Although there is much evidence that activating mental representations of attachments figure is beneficial for psychological health and can reduce stress response, no research has directly investigated whether attachment activation can ameliorate hormonal stress response. This study investigated whether activating an attachment figure or a non-attachment figure following administration of a socially evaluated cold pressor test to elicit stress impacted on glucocorticoid and noradrenergic response. Participants (N = 61) provided baseline salivary samples, underwent a cold pressor test, then imagined an attachment or non-attachment figure, and finally provided subsequent saliva samples. Participants who imagined a non-attachment figure had greater noradrenergic response following the stressor than those who imagined an attachment figure. These findings highlight that activating attachment representations can ameliorate the immediate noradrenergic stress response. PMID:26115145

  20. Noradrenergic modulation of emotional memory in aging.

    PubMed

    Mammarella, Nicola; Di Domenico, Alberto; Palumbo, Rocco; Fairfield, Beth

    2016-05-01

    Interest in the role of the noradrenergic system in the modulation of emotional memories has recently increased. This study briefly reviews this timely line of research with a specific focus on aging. After having identified surprisingly few studies that investigated emotional memory in older adults from a neurobiological perspective, we found a significant interaction between noradrenergic activity and emotional memory enhancement in older adults. This pattern of data are explained both in terms of a top-down modulation of behavioral processes (e.g., changes in priority and individual goals) and in terms of greater activity of noradrenergic system during aging. Altogether, both behavioral and genetic variations studies (e.g., Alpha 2 B Adrenoceptor genotype) have shown that healthy older adults are able to circumvent or minimize the experience of negative emotions and stabilize or even enhance positive emotional experiences. Future studies are highly warranted to better clarify the relationship between noradrenaline and emotional memories in the aging brain. PMID:27003374

  1. Limbic circuitry of the midline thalamus.

    PubMed

    Vertes, Robert P; Linley, Stephanie B; Hoover, Walter B

    2015-07-01

    The thalamus was subdivided into three major groups: sensorimotor nuclei (or principal/relay nuclei), limbic nuclei and nuclei bridging these two domains. Limbic nuclei of thalamus (or 'limbic thalamus') consist of the anterior nuclei, midline nuclei, medial division of the mediodorsal nucleus (MDm) and central medial nucleus (CM) of the intralaminar complex. The midline nuclei include the paraventricular (PV) and paratenial (PT) nuclei, dorsally, and the reuniens (RE) and rhomboid (RH) nuclei, ventrally. The 'limbic' thalamic nuclei predominantly connect with limbic-related structures and serve a direct role in limbic-associated functions. Regarding the midline nuclei, RE/RH mainly target limbic cortical structures, particularly the hippocampus and the medial prefrontal cortex. Accordingly, RE/RH participate in functions involving interactions of the HF and mPFC. By contrast, PV/PT mainly project to limbic subcortical structures, particularly the amygdala and nucleus accumbens, and hence are critically involved in affective behaviors such as stress/anxiety, feeding behavior, and drug seeking activities. The anatomical/functional characteristics of MDm and CM are very similar to those of the midline nuclei and hence the collection of nuclei extending dorsoventrally along the midline/paramidline of the thalamus constitute the core of the 'limbic thalamus'. PMID:25616182

  2. LIMBIC CIRCUITRY OF THE MIDLINE THALAMUS

    PubMed Central

    Vertes, Robert P.; Linley, Stephanie B.; Hoover, Walter B.

    2016-01-01

    The thalamus was subdivided into three major groups: sensorimotor nuclei (or principal/relay nuclei), limbic nuclei and nuclei bridging these two domains. Limbic nuclei of thalamus (or ‘limbic thalamus’) consist of the anterior nuclei, midline nuclei, medial division of the mediodorsal nucleus (MDm) and central medial nucleus (CM) of the intralaminar complex. The midline nuclei include the paraventricular (PV) and paratenial (PT) nuclei, dorsally, and the reuniens (RE) and rhomboid (RH) nuclei, ventrally. The ‘limbic’ thalamic nuclei predominantly connect with limbic-related structures and serve a direct role in limbic–associated functions. Regarding the midline nuclei, RE/RH mainly target limbic cortical structures, particularly the hippocampus and the medial prefrontal cortex. Accordingly, RE/RH participate in functions involving interactions of the HF and mPFC. By contrast, PV/PT mainly project to limbic subcortical structures, particularly the amygdala and nucleus accumbens, and hence are critically involved in affective behaviors such as stress/anxiety, feeding behavior, and drug seeking activities. The anatomical/functional characteristics of MDm and CM are very similar to those of the midline nuclei and hence the collection of nuclei extending dorsoventrally along the midline/paramidline of the thalamus constitute the core of the ‘limbic thalamus’. PMID:25616182

  3. Noradrenergic enhancement of amygdala responses to fear

    PubMed Central

    Onur, Oezguer A.; Walter, Henrik; Schlaepfer, Thomas E.; Rehme, Anne K.; Schmidt, Christoph; Keysers, Christian; Maier, Wolfgang

    2009-01-01

    Multiple lines of evidence implicate the basolateral amygdala (BLA) and the noradrenergic (norepinephrine, NE) system in responding to stressful stimuli such as fear signals, suggesting hyperfunction of both in the development of stress-related pathologies including anxiety disorders. However, no causative link between elevated NE neurotransmission and BLA hyperresponsiveness to fear signals has been established to date in humans. To determine whether or not increased noradrenergic tone enhances BLA responses to fear signals, we used functional magnetic resonance imaging (fMRI) and a strategy of pharmacologically potentiating NE neurotransmission in healthy volunteers. 18 subjects were scanned two times on a facial emotion paradigm and given either a single-dose placebo or 4 mg of the selective NE reuptake inhibitor reboxetine 2 h prior to an fMRI session. We found that reboxetine induced an amygdala response bias towards fear signals that did not exist at placebo baseline. This pharmacological effect was probabilistically mapped to the BLA. Extrapolation of our data to conditions of traumatic stress suggests that disinhibited endogenous NE signaling could serve as a crucial etiological contributor to post-traumatic stress disorder (PTSD) by eliciting exaggerated BLA responses to fear signals. PMID:19246474

  4. PERVASIVE OLFACTORY IMPAIRMENT AFTER BILATERAL LIMBIC SYSTEM DESTRUCTION

    PubMed Central

    Tranel, Daniel; Welsh-Bohmer, Kathleen A.

    2012-01-01

    What pattern of brain damage could completely obliterate the sense of olfaction in humans? We had an opportunity to address this intriguing question in patient B., who has extensive bilateral damage to most of the limbic system, including the medial and lateral temporal lobes, orbital frontal cortex, insular cortex, anterior cingulate cortex, and basal forebrain, caused by herpes simplex encephalitis. The patient demonstrated profound impairments in odor identification and recognition. Moreover, he could not discriminate between olfactory stimuli and he had severe impairments in odor detection. Reliable stimulus detection was obtained only for solutions of the organic solvent acetone and highly concentrated solutions of ethanol. In contrast to the more circumscribed olfactory deficits demonstrated in patients with damage confined to either the temporal lobes or orbitofrontal cortex (which tend to involve odor identification but not odor detection), patient B. demonstrates a strikingly severe and complete anosmia. This contrast in olfactory abilities and deficits as a result of different anatomical pathology affords new insights into the neural substrates of olfactory processing in humans. PMID:22220560

  5. Evidence for alterations in central noradrenergic signaling in irritable bowel syndrome*, **

    PubMed Central

    Berman, Steven; Suyenobu, Brandall; Naliboff, Bruce D.; Bueller, Joshua; Stains, Jean; Wong, Heng; Mandelkern, Mark; Fitzgerald, Leah; Ohning, Gordon; Gupta, Arpana; Labus, Jennifer S.; Tillisch, Kirsten; Mayer, Emeran A.

    2014-01-01

    Background/aims Alterations in noradrenergic (NE) signaling have been implicated in the pathophysiology of irritable bowel syndrome (IBS), and adrenergic receptors are potential treatment targets. Methods To characterize central NE signaling in IBS, 11 patients and 11 healthy controls (HCs) were studied 3 times during an auditory oddball vigilance task after double-blind ingestion of the α2-adrenoreceptor (α2AR) antagonist yohimbine (YOH), the α2AR agonist clonidine (CLO), or placebo (PLA). Regional cerebral glucose metabolism was measured with [18F] fluorodeoxyglucose (FDG) positron emission tomography (PET). Measures of anxiety, early-life trauma, plasma NE and blood pressure were acquired. Results Patients had higher plasma NE levels than HCs before and after ingestion of all drugs (all p <0.05). YOH increased plasma NE and more anxiety in patients than in HCs. After YOH, NE levels directly correlated with drug-induced increases in anxiety in IBS patients (r=0.61), but not in HCs. IBS patients showed less YOH-mediated reduction of activity in a central arousal circuit, consistent with fewer functional presynaptic α2AR. In HCs, but not in patients, activation of amygdala and subgenual anterior cingulate cortex (sgACC) was inversely correlated with activation of anterior mid cingulate cortex (aMCC), and state anxiety covaried directly with activity in limbic and right frontotemporal cortices, but indirectly with activity in the left frontotemporal cortex. YOH-mediated reduction of activity in brainstem and amygdala inversely correlated with early life trauma. Conclusions IBS patients showed evidence for increased noradrenergic activity consistent with downregulation of presynaptic inhibitory α2ARs. Activity within central arousal circuits was biased toward greater excitability and reduced corticolimbic inhibition in IBS. Early life trauma may be one mediator of these abnormalities. PMID:22917679

  6. What birdsong can teach us about the central noradrenergic system

    PubMed Central

    Castelino, Christina B; Schmidt, Marc F

    2011-01-01

    Increasing evidence indicates that the noradrenergic system plays a key role in biasing the nervous system towards producing behaviors that help animals adapt to constantly changing environments. Most of the studies investigating noradrenergic function are performed in animals that have a limited repertoire of tractable natural behaviors. Songbirds, in contrast, with their rich set of precisely quantifiable vocal behaviors, provide a unique model system to study the noradrenergic system. An additional advantage of this system is the existence of a well-defined neural circuit, known as the song system, that is necessary for the production, learning and perception of song and can be studied at many different levels. These include the ability to investigate the effect of norepinephrine on synaptic function using brain slices, identifying its influence on singing-related gene expression and monitoring its impact on the activity of single neurons recorded in awake behaving birds. In this review article, we describe the similarities and differences, both anatomical and functional, between the avian and mammalian noradrenergic system and its role in sensory processing, learning, attention and synaptic modulation. We also describe how the noradrenergic system influences motor production, an under-explored aspect of norepinephrine function in mammalian studies. We argue that the richness of behaviors observed in songbirds provides a unique opportunity to study the noradrenergic system in a highly integrative manner that will ultimately provide important insights in the role of this system in normal behavior and disease. PMID:19686836

  7. Primary cilia and forebrain development.

    PubMed

    Willaredt, Marc August; Tasouri, Evangelia; Tucker, Kerry L

    2013-01-01

    With a microtubule-based axoneme supporting its plasma membrane-ensheathed projection from the basal body of almost all cell types in the human body, and present in only one copy per cell, the primary cilium can be considered an organelle sui generis. Although it was first observed and recorded in histological studies from the late 19th century, the tiny structure was essentially forgotten for many decades. In the past ten years, however, scientists have turned their eyes once again upon primary cilia and realized that they are very important for the development of almost all organs in the mammalian body, especially those dependent upon the signaling from members Hedgehog family, such as Indian and Sonic hedgehog. In this review, we outline the roles that primary cilia play in forebrain development, not just in the crucial transduction of Sonic hedgehog signaling, but also new results showing that cilia are important for cell cycle progression in proliferating neural precursors. We will focus upon cerebral cortex development but will also discuss the importance of cilia for the embryonic hippocampus, olfactory bulb, and diencephalon. PMID:23085524

  8. Dopamine systems in the forebrain

    PubMed Central

    Cave, John W.; Baker, Harriet

    2009-01-01

    The brain contains a number of distinct regions that share expression of dopamine (DA) and its requisite biosynthetic machinery, but otherwise encompass a diverse array of features and functions. Across the vertebrate family, the olfactory bulb (OB) contains the major DA system in the forebrain. OB DA cells are primarily periglomerular interneurons that define the glomerular structures in which they receive innervation from olfactory receptor neurons as well as mitral and tufted cells, the primary OB output neurons. The OB DA cells are necessary for both discrimination and the dynamic range over which odorant sensory information can be detected. In the embryo, OB DA neurons are derived from the ventricular area of the evaginating telencephalon, the dorsal lateral ganglionic eminence, and the septum. However, most OB DA interneurons are generated post-natally and continue to be produced throughout adult life from neural stem cells in the subventricular zone of the lateral ventricle and rostral migratory stream. Adult born OB DA neurons are capable of integrating into existing circuits and do not appear to degenerate in Parkinson’s disease. Several genes have been identified that regulate the differentiation of OB DA interneurons from neural stem cells. These include transcription factors that modify the expression of tyrosine hydroxylase, the first enzyme in the DA biosynthetic pathway and a reliable marker of the DA phenotype. Elucidation of the molecular genetic pathways of OB DA differentiation may advance the development of strategies to treat neurological disease. PMID:19731547

  9. Low dose naltrexone administration in morphine dependent rats attenuates withdrawal-induced norepinephrine efflux in forebrain

    PubMed Central

    Van Bockstaele, Elisabeth J.; Qian, Yaping; Sterling, Robert C.; Page, Michelle E.

    2009-01-01

    experiment, animals were transcardially perfused and the brains were removed for verification of probe placement. Low dose naltrexone pre-treatment significantly attenuated withdrawal-induced increases of extracellular norepinephrine in the BNST, with a smaller effect in the FC. These findings suggest that alterations in norepinephrine release associated with withdrawal may be attenuated in forebrain targets of noradrenergic brainstem neurons that may underlie reduced behavioral signs of withdrawal following low dose naltrexone administration. PMID:18367303

  10. Progressive limbic encephalopathy: Problems and prospects

    PubMed Central

    Chandra, Sadanandavalli Retnaswami; Seshadri, Roopa; Chikabasaviah, Yasha; Issac, Thomas Gregor

    2014-01-01

    Background: It was observed that a good number of patients presenting with psychiatric manifestations when investigated later because of unresponsiveness to treatment or late development of organic features turned out to be treatable limbic syndromes. Introduction: The aim of this study is to assess the patients presenting with new onset neuropsychiatric symptoms satisfying the criteria for probable limbic encephalitis. Patients and Methods: Patients referred to neurology department following a period of treatment for neuropsychiatric symptoms, which did not respond to conventional treatment were analyzed using Electroencephalography (EEG), magnetic resonance imaging, cerebrospinal fluid, screening for malignancy Vasculitic work-up, histopathology and autoantibody done when feasible. Results: There were 22 patients satisfying criteria for probable limbic encephalitis. Their mean age was 34.5 years. Symptoms varied from unexplained anxiety, panic and depression, lack of inhibition, wandering, incontinence, myoclonus, seizures and stroke like episodes. Three had systemic malignancy, 10 had chronic infection, one each with vasculitis, acute disseminated encephalomyelitis, Hashimoto encephalitis and two each with non-convulsive status, cryptogenic and Idiopathic inflammation. Conclusion: All patients who present with new onset neuropsychiatric symptoms need to be evaluated for sub-acute infections, inflammation, autoimmune limbic encephalitis and paraneoplastic syndrome. A repeated 20 minute EEG is a very effective screening tool to detect organicity. PMID:25024566

  11. GABAergic synchronization in the limbic system and its role in the generation of epileptiform activity

    PubMed Central

    Avoli, Massimo; de Curtis, Marco

    2016-01-01

    GABA is the main inhibitory neurotransmitter in the adult forebrain, where it activates ionotropic type A and metabotropic type B receptors. Early studies have shown that GABAA receptor-mediated inhibition controls neuronal excitability and thus the occurrence of seizures. However, more complex, and at times unexpected, mechanisms of GABAergic signaling have been identified during epileptiform discharges over the last few years. Here, we will review experimental data that point at the paradoxical role played by GABAA receptor-mediated mechanisms in synchronizing neuronal networks, and in particular those of limbic structures such as the hippocampus, the entorhinal and perirhinal cortices, or the amygdala. After having summarized the fundamental characteristics of GABAA receptor-mediated mechanisms, we will analyze their role in the generation of network oscillations and their contribution to epileptiform synchronization. Whether and how GABAA receptors influence the interaction between limbic networks leading to ictogenesis will be also reviewed. Finally, we will consider the role of altered inhibition in the human epileptic brain along with the ability of GABAA receptor-mediated conductances to generate synchronous depolarizing events that may lead to ictogenesis in human epileptic disorders as well. PMID:21802488

  12. Basal forebrain projections to the lateral habenula modulate aggression reward.

    PubMed

    Golden, Sam A; Heshmati, Mitra; Flanigan, Meghan; Christoffel, Daniel J; Guise, Kevin; Pfau, Madeline L; Aleyasin, Hossein; Menard, Caroline; Zhang, Hongxing; Hodes, Georgia E; Bregman, Dana; Khibnik, Lena; Tai, Jonathan; Rebusi, Nicole; Krawitz, Brian; Chaudhury, Dipesh; Walsh, Jessica J; Han, Ming-Hu; Shapiro, Matt L; Russo, Scott J

    2016-06-30

    Maladaptive aggressive behaviour is associated with a number of neuropsychiatric disorders and is thought to result partly from the inappropriate activation of brain reward systems in response to aggressive or violent social stimuli. Nuclei within the ventromedial hypothalamus, extended amygdala and limbic circuits are known to encode initiation of aggression; however, little is known about the neural mechanisms that directly modulate the motivational component of aggressive behaviour. Here we established a mouse model to measure the valence of aggressive inter-male social interaction with a smaller subordinate intruder as reinforcement for the development of conditioned place preference (CPP). Aggressors develop a CPP, whereas non-aggressors develop a conditioned place aversion to the intruder-paired context. Furthermore, we identify a functional GABAergic projection from the basal forebrain (BF) to the lateral habenula (lHb) that bi-directionally controls the valence of aggressive interactions. Circuit-specific silencing of GABAergic BF-lHb terminals of aggressors with halorhodopsin (NpHR3.0) increases lHb neuronal firing and abolishes CPP to the intruder-paired context. Activation of GABAergic BF-lHb terminals of non-aggressors with channelrhodopsin (ChR2) decreases lHb neuronal firing and promotes CPP to the intruder-paired context. Finally, we show that altering inhibitory transmission at BF-lHb terminals does not control the initiation of aggressive behaviour. These results demonstrate that the BF-lHb circuit has a critical role in regulating the valence of inter-male aggressive behaviour and provide novel mechanistic insight into the neural circuits modulating aggression reward processing. PMID:27357796

  13. Physical exercise affects attentional orienting behavior through noradrenergic mechanisms.

    PubMed

    Robinson, Andrea M; Buttolph, Thomas; Green, John T; Bucci, David J

    2015-06-01

    Spontaneously hypertensive rats (SHRs), a commonly used animal model of attention-deficit/hyperactivity disorder, exhibit little habituation of the orienting response to repeated presentations of a nonreinforced visual stimulus. However, SHRs that have access to a running wheel for 5, 10, or 21 days exhibit robust habituation that is indistinguishable from normo-active rats. Two days of exercise, in comparison, is not sufficient to affect habituation. Here we tested the hypothesis that the effect of exercise on orienting behavior in SHRs is mediated by changes in noradrenergic function. In Experiment 1, we found that 5, 10, or 21 days of access to a running wheel, but not 2 days, significantly reduced levels of the norepinephrine transporter in medial prefrontal cortex. In Experiment 2, we tested for a causal relationship between changes in noradrenergic function and orienting behavior by blocking noradrenergic receptors during exercise. Rats that received propranolol (beta adrenergic/noradrenergic receptor blocker) during 10 days of exercise failed to exhibit an exercise-induced reduction in orienting behavior. The results inform a growing literature regarding the effects of exercise on behavior and the potential use of exercise as a treatment for mental disorders. PMID:26030434

  14. Effects of abstinence from chronic cocaine self-administration on nonhuman primate dorsal and ventral noradrenergic bundle terminal field structures.

    PubMed

    Smith, Hilary R; Beveridge, Thomas J R; Nader, Michael A; Porrino, Linda J

    2016-06-01

    Repeated exposure to cocaine is known to dysregulate the norepinephrine system, and norepinephrine has also been implicated as having a role in abstinence and withdrawal. The goal of this study was to determine the effects of exposure to cocaine self-administration and subsequent abstinence on regulatory elements of the norepinephrine system in the nonhuman primate brain. Rhesus monkeys self-administered cocaine (0.3 mg/kg/injection, 30 reinforcers/session) under a fixed-interval 3-min schedule of reinforcement for 100 sessions. Animals in the abstinence group then underwent a 30-day period during which no operant responding was conducted, followed by a final session of operant responding. Control animals underwent identical schedules of food reinforcement and abstinence. This duration of cocaine self-administration has been shown previously to increase levels of norepinephrine transporters (NET) in the ventral noradrenergic bundle terminal fields. In contrast, in the current study, abstinence from chronic cocaine self-administration resulted in elevated levels of [(3)H]nisoxetine binding to the NET primarily in dorsal noradrenergic bundle terminal field structures. As compared to food reinforcement, chronic cocaine self-administration resulted in decreased binding of [(3)H]RX821002 to α2-adrenoceptors primarily in limbic-related structures innervated by both dorsal and ventral bundles, as well as elevated binding in the striatum. However, following abstinence from responding for cocaine binding to α2-adrenoceptors was not different than in control animals. These data demonstrate the dynamic nature of the regulation of norepinephrine during cocaine use and abstinence, and provide further evidence that the norepinephrine system should not be overlooked in the search for effective pharmacotherapies for cocaine dependence. PMID:26013302

  15. Norepinephrine transport-mediated gene expression in noradrenergic neurogenesis

    PubMed Central

    Hu, Yao Fei; Caron, Marc G; Sieber-Blum, Maya

    2009-01-01

    Background We have identified a differential gene expression profile in neural crest stem cells that is due to deletion of the norepinephrine transporter (NET) gene. NET is the target of psychotropic substances, such as tricyclic antidepressants and the drug of abuse, cocaine. NET mutations have been implicated in depression, anxiety, orthostatic intolerance and attention deficit hyperactivity disorder (ADHD). NET function in adult noradrenergic neurons of the peripheral and central nervous systems is to internalize norepinephrine from the synaptic cleft. By contrast, during embryogenesis norepinephrine (NE) transport promotes differentiation of neural crest stem cells and locus ceruleus progenitors into noradrenergic neurons, whereas NET inhibitors block noradrenergic differentiation. While the structure of NET und the regulation of NET function are well described, little is known about downstream target genes of norepinephrine (NE) transport. Results We have prepared gene expression profiles of in vitro differentiating wild type and norepinephrine transporter-deficient (NETKO) mouse neural crest cells using long serial analysis of gene expression (LongSAGE). Comparison analyses have identified a number of important differentially expressed genes, including genes relevant to neural crest formation, noradrenergic neuron differentiation and the phenotype of NETKO mice. Examples of differentially expressed genes that affect noradrenergic cell differentiation include genes in the bone morphogenetic protein (BMP) signaling pathway, the Phox2b binding partner Tlx2, the ubiquitin ligase Praja2, and the inhibitor of Notch signaling, Numbl. Differentially expressed genes that are likely to contribute to the NETKO phenotype include dopamine-β-hydroxylase (Dbh), tyrosine hydroxylase (Th), the peptide transmitter 'cocaine and amphetamine regulated transcript' (Cart), and the serotonin receptor subunit Htr3a. Real-time PCR confirmed differential expression of key genes not

  16. Descending motor pathways and the spinal motor system - Limbic and non-limbic components

    NASA Technical Reports Server (NTRS)

    Holstege, Gert

    1991-01-01

    Research on descending motor pathways to caudal brainstem and spinal cord in the spinal motor system is reviewed. Particular attention is given to somatic and autonomic motoneurons in the spinal cord and brainstem, local projections to motoneurons, bulbospinal interneurons projecting to motoneurons, descending pathways of somatic motor control systems, and descending pathways involved in limbic motor control systems.

  17. Noradrenergic involvement in pinealectomy induced convulsions in gerbils.

    PubMed

    Champney, T H

    1990-12-11

    Gerbils treated with various noradrenergic compounds were pinealectomized (PINX) or sham-operated (SHAM) and observed for convulsive activity. Although declines in cortical and hypothalamic norepinephrine content were found after alpha-methylparatyrosine (alpha MPT) or PINX, treatment with alpha MPT did not produce convulsions in SHAM gerbils or in gerbils which were PINX one week earlier. Likewise, alpha MPT did not increase the number or severity of convulsions observed in acutely PINX gerbils. Treatment with propranolol or isoproterenol did not have any effect on convulsive activity of PINX gerbils, except that isoproterenol increased the excitability of all the gerbils. In conclusion, reducing catecholamine content or modifying beta-noradrenergic receptor activity was not able to alter the convulsive activity which occurs after acute PINX. PMID:2293111

  18. Vascular Mural Cells Promote Noradrenergic Differentiation of Embryonic Sympathetic Neurons.

    PubMed

    Fortuna, Vitor; Pardanaud, Luc; Brunet, Isabelle; Ola, Roxana; Ristori, Emma; Santoro, Massimo M; Nicoli, Stefania; Eichmann, Anne

    2015-06-23

    The sympathetic nervous system controls smooth muscle tone and heart rate in the cardiovascular system. Postganglionic sympathetic neurons (SNs) develop in close proximity to the dorsal aorta (DA) and innervate visceral smooth muscle targets. Here, we use the zebrafish embryo to ask whether the DA is required for SN development. We show that noradrenergic (NA) differentiation of SN precursors temporally coincides with vascular mural cell (VMC) recruitment to the DA and vascular maturation. Blocking vascular maturation inhibits VMC recruitment and blocks NA differentiation of SN precursors. Inhibition of platelet-derived growth factor receptor (PDGFR) signaling prevents VMC differentiation and also blocks NA differentiation of SN precursors. NA differentiation is normal in cloche mutants that are devoid of endothelial cells but have VMCs. Thus, PDGFR-mediated mural cell recruitment mediates neurovascular interactions between the aorta and sympathetic precursors and promotes their noradrenergic differentiation. PMID:26074079

  19. Noradrenergic control of error perseveration in medial prefrontal cortex

    PubMed Central

    Caetano, Marcelo S.; Jin, Lu E.; Harenberg, Linda; Stachenfeld, Kimberly L.; Arnsten, Amy F. T.; Laubach, Mark

    2013-01-01

    The medial prefrontal cortex (mPFC) plays a key role in behavioral variability, action monitoring, and inhibitory control. The functional role of mPFC may change over the lifespan due to a number of aging-related issues, including dendritic regression, increased cAMP signaling, and reductions in the efficacy of neuromodulators to influence mPFC processing. A key neurotransmitter in mPFC is norepinephrine. Previous studies have reported aging-related changes in the sensitivity of mPFC-dependent tasks to noradrenergic agonist drugs, such as guanfacine. Here, we assessed the effects of yohimbine, an alpha-2 noradrenergic antagonist, in cohorts of younger and older rats in a classic test of spatial working memory (using a T-maze). Older rats (23–29 mo.) were impaired by a lower dose of yohimbine compared to younger animals (5–10 mo.). To determine if the drug acts on alpha-2 noradrenergic receptors in mPFC and if its effects are specific to memory-guided performance, we made infusions of yohimbine into mPFC of a cohort of young rats (6 mo.) using an operant delayed response task. The task involved testing rats in blocks of trials with memory- and stimulus-guided performance. Yohimbine selectively impaired memory-guided performance and was associated with error perseveration. Infusions of muscimol (a GABA-A agonist) at the same sites also selectively impaired memory-guided performance, but did not lead to error perseveration. Based on these results, we propose several potential interpretations for the role for the noradrenergic system in the performance of delayed response tasks, including the encoding of previous response locations, task rules (i.e., using a win-stay strategy instead of a win-shift strategy), and performance monitoring (e.g., prospective encoding of outcomes). PMID:23293590

  20. Noradrenergic control of error perseveration in medial prefrontal cortex.

    PubMed

    Caetano, Marcelo S; Jin, Lu E; Harenberg, Linda; Stachenfeld, Kimberly L; Arnsten, Amy F T; Laubach, Mark

    2012-01-01

    The medial prefrontal cortex (mPFC) plays a key role in behavioral variability, action monitoring, and inhibitory control. The functional role of mPFC may change over the lifespan due to a number of aging-related issues, including dendritic regression, increased cAMP signaling, and reductions in the efficacy of neuromodulators to influence mPFC processing. A key neurotransmitter in mPFC is norepinephrine. Previous studies have reported aging-related changes in the sensitivity of mPFC-dependent tasks to noradrenergic agonist drugs, such as guanfacine. Here, we assessed the effects of yohimbine, an alpha-2 noradrenergic antagonist, in cohorts of younger and older rats in a classic test of spatial working memory (using a T-maze). Older rats (23-29 mo.) were impaired by a lower dose of yohimbine compared to younger animals (5-10 mo.). To determine if the drug acts on alpha-2 noradrenergic receptors in mPFC and if its effects are specific to memory-guided performance, we made infusions of yohimbine into mPFC of a cohort of young rats (6 mo.) using an operant delayed response task. The task involved testing rats in blocks of trials with memory- and stimulus-guided performance. Yohimbine selectively impaired memory-guided performance and was associated with error perseveration. Infusions of muscimol (a GABA-A agonist) at the same sites also selectively impaired memory-guided performance, but did not lead to error perseveration. Based on these results, we propose several potential interpretations for the role for the noradrenergic system in the performance of delayed response tasks, including the encoding of previous response locations, task rules (i.e., using a win-stay strategy instead of a win-shift strategy), and performance monitoring (e.g., prospective encoding of outcomes). PMID:23293590

  1. Noradrenergic regulation of fear and drug-associated memory reconsolidation.

    PubMed

    Otis, James M; Werner, Craig T; Mueller, Devin

    2015-03-01

    Emotional and traumatic experiences lead to the development of particularly strong memories that can drive neuropsychiatric disorders, such as posttraumatic stress disorder (PTSD) and drug addiction. Disruption of these memories would therefore serve as a powerful treatment option, and targeting the pathologic emotional, but not declarative, component of a memory would be ideal for clinical intervention. Research reveals that after retrieval of a consolidated memory, the memory can be destabilized, and must then be reconsolidated through synaptic plasticity to allow subsequent retrieval. Disruption of reconsolidation-related plasticity would therefore impair specific, reactivated memories. Noradrenergic signaling strengthens synaptic plasticity and is essential for encoding the emotional components of memory. Consistent with this, investigations have now revealed that noradrenergic signaling is a critical mechanism for reconsolidation of emotional memories in rodent and human models. Here, we discuss these investigations and promising clinical trials indicating that disruption of noradrenergic signaling during reconsolidation may abolish the pathologic emotional, but not declarative, component of memories allowing alleviation of neuropsychiatric disorders including PTSD and drug addiction. PMID:25315025

  2. Fast Modulation of Visual Perception by Basal Forebrain Cholinergic Neurons

    PubMed Central

    Estandian, Daniel; Xu, Min; Kwan, Alex C.; Lee, Seung-Hee; Harrison, Thomas C.; Feng, Guoping; Dan, Yang

    2014-01-01

    The basal forebrain provides the primary source of cholinergic input to the cortex, and it plays a crucial role in promoting wakefulness and arousal. However, whether rapid changes in basal forebrain neuron spiking in awake animals can dynamically influence sensory perception is unclear. Here we show that basal forebrain cholinergic neurons rapidly regulate cortical activity and visual perception in awake, behaving mice. Optogenetic activation of the cholinergic neurons or their V1 axon terminals improved performance of a visual discrimination task on a trial-by-trial basis. In V1, basal forebrain activation enhanced visual responses and desynchronized neuronal spiking, which could partly account for the behavioral improvement. Conversely, optogenetic basal forebrain inactivation decreased behavioral performance, synchronized cortical activity and impaired visual responses, indicating the importance of cholinergic activity in normal visual processing. These results underscore the causal role of basal forebrain cholinergic neurons in fast, bidirectional modulation of cortical processing and sensory perception. PMID:24162654

  3. Uncovering diversity in the development of central noradrenergic neurons and their efferents.

    PubMed

    Robertson, Sabrina D; Plummer, Nicholas W; Jensen, Patricia

    2016-06-15

    Uncovering the mechanisms that underlie central noradrenergic neuron heterogeneity is essential to understanding selective subtype vulnerability to disease and environmental insult. Using recombinase-based intersectional genetic fate mapping we have previously demonstrated that molecularly distinct progenitor populations give rise to mature noradrenergic neurons differing in their anatomical location, axon morphology and efferent projection pattern. Here we review the findings from our previous study and extend our analysis of the noradrenergic subpopulation defined by transient developmental expression of Hoxb1. Using a combination of intersectional genetic fate mapping and analysis of a targeted loss of function mutation in Hoxb1, we have now uncovered additional heterogeneity based on the requirement of some noradrenergic neurons for Hoxb1 expression. By comparing the distribution of noradrenergic neurons derived from the Hoxb1 expression domain in wild-type and mutant mice, we demonstrate that Hoxb1 expression is required by a subset of neurons in the pons. Additional fate mapping, using a Hoxb1 enhancer element that drives Cre recombinase expression exclusively in rhombomere 4 of the hindbrain, reveals the existence of a subpopulation of noradrenergic neurons in the pons with more restricted axonal targets than the full Hoxb1-derived subpopulation. The unique projection profile of this newly defined subpopulation suggests that it may be functionally distinct. These analyses shed new light on the molecular determinants of noradrenergic identity in the pons and the overall complexity of the central noradrenergic system. This article is part of a Special Issue entitled SI: Noradrenergic System. PMID:26612521

  4. Selective activation of cholinergic basal forebrain neurons induces immediate sleep-wake transitions.

    PubMed

    Han, Yong; Shi, Yu-feng; Xi, Wang; Zhou, Rui; Tan, Zhi-bing; Wang, Hao; Li, Xiao-ming; Chen, Zhong; Feng, Guoping; Luo, Minmin; Huang, Zhi-li; Duan, Shumin; Yu, Yan-qin

    2014-03-17

    The basal forebrain (BF) plays a crucial role in cortical activation [1, 2]. However, the exact role of cholinergic BF (ch-BF) neurons in the sleep-wake cycle remains unclear [3, 4]. We demonstrated that photostimulation of ch-BF neurons genetically targeted with channelrhodopsin 2 (ChR2) was sufficient to induce an immediate transition to waking or rapid eye movement (REM) sleep from slow-wave sleep (SWS). Light stimulation was most likely to induce behavioral arousal during SWS, but not during REM sleep, a result in contrast to the previously reported photostimulation of noradrenergic or hypocretin neurons that induces wake transitions from both SWS and REM sleep. Furthermore, the ratio of light-induced transitions from SWS to wakefulness or to REM sleep did not significantly differ from that of natural transitions, suggesting that activation of ch-BF neurons facilitates the transition from SWS but does not change the direction of the transition. Excitation of ch-BF neurons during wakefulness or REM sleep sustained the cortical activation. Stimulation of these neurons for 1 hr induced a delayed increase in the duration of wakefulness in the subsequent inactive period. Our results suggest that activation of ch-BF neurons alone is sufficient to suppress SWS and promote wakefulness and REM sleep. PMID:24613308

  5. Limbic but not non-limbic kindling impairs conditioned fear and promotes plasticity of NPY and its Y2 receptor.

    PubMed

    Botterill, J J; Guskjolen, A J; Marks, W N; Caruncho, H J; Kalynchuk, L E

    2015-11-01

    Epileptic seizures negatively affect cognition. However, the mechanisms that contribute to cognitive impairments after seizures are largely unknown. Here, we examined the effects of long-term kindling (i.e., 99 stimulations) of limbic (basolateral amygdala, dorsal hippocampus) and non-limbic (caudate nucleus) brain sites on conditioned fear and hippocampal plasticity. We first showed that kindling had no effect on acquisition of a hippocampal-dependent trace fear-conditioning task but limbic kindling impaired the retrieval of these fear memories. To determine the relationship between memory and hippocampal neuronal activity, we examined the expression of Fos protein 90 min after memory retrieval (i.e., 4 days after the last kindling stimulation). We found that limbic kindling, but not non-limbic kindling, decreased Fos expression in the granule cell layer, hilus, CA3 pyramidal cell layer, and CA1 pyramidal cell layer. Next, to investigate a mechanism that could contribute to dampen hippocampal neuronal activity in limbic-kindled rats, we focused on the endogenous anticonvulsant neuropeptide Y (NPY), which is expressed in a subset of GABAergic interneurons and can prevent glutamate release through interactions with its Y2 receptor. We found that limbic kindling significantly decreased the number of NPY-immunoreactive cells in several hippocampal subfields despite minimal staining of the neurodegenerative marker Fluoro-Jade B. However, we also noted that limbic kindling enhanced NPY immunoreactivity throughout the mossy fiber pathway. In these same regions, we observed limbic kindling-induced de novo expression of the NPY Y2 receptor. These novel findings demonstrate the site-specific effects of kindling on cognition and NPY plasticity, and they provide evidence that altered hippocampal NPY after limbic seizures coincides with dampened neural activity and cognitive impairments. PMID:25146309

  6. Pre-frontal control of closed-loop limbic neurostimulation by rodents using a brain-computer interface

    NASA Astrophysics Data System (ADS)

    Widge, Alik S.; Moritz, Chet T.

    2014-04-01

    Objective. There is great interest in closed-loop neurostimulators that sense and respond to a patient's brain state. Such systems may have value for neurological and psychiatric illnesses where symptoms have high intraday variability. Animal models of closed-loop stimulators would aid preclinical testing. We therefore sought to demonstrate that rodents can directly control a closed-loop limbic neurostimulator via a brain-computer interface (BCI). Approach. We trained rats to use an auditory BCI controlled by single units in prefrontal cortex (PFC). The BCI controlled electrical stimulation in the medial forebrain bundle, a limbic structure involved in reward-seeking. Rigorous offline analyses were performed to confirm volitional control of the neurostimulator. Main results. All animals successfully learned to use the BCI and neurostimulator, with closed-loop control of this challenging task demonstrated at 80% of PFC recording locations. Analysis across sessions and animals confirmed statistically robust BCI control and specific, rapid modulation of PFC activity. Significance. Our results provide a preliminary demonstration of a method for emotion-regulating closed-loop neurostimulation. They further suggest that activity in PFC can be used to control a BCI without pre-training on a predicate task. This offers the potential for BCI-based treatments in refractory neurological and mental illness.

  7. Pre-frontal control of closed-loop limbic neurostimulation by rodents using a brain-computer interface

    PubMed Central

    Widge, Alik S.; Moritz, Chet T.

    2015-01-01

    Objective There is great interest in closed-loop neurostimulators that sense and respond to a patient’s brain state. Such systems may have value for neurological and psychiatric illnesses where symptoms have high intraday variability. Animal models of closed-loop stimulators would aid preclinical testing. We sought to demonstrate that rodents can directly control a closed-loop limbic neurostimulator via a brain-computer interface (BCI). Approach We trained rats to use an auditory BCI controlled by single units in prefrontal cortex (PFC). The BCI controlled electrical stimulation in the medial forebrain bundle (MFB), a limbic structure involved in reward-seeking. Rigorous offline analyses were performed to confirm volitional control of the neurostimulator. Main Results All animals successfully learned to use the BCI and neurostimulator, with closed-loop control of this challenging task demonstrated at 80% of PFC recording locations. Analysis across sessions and animals confirmed statistically robust BCI control and specific, rapid modulation of PFC activity. Significance Our results provide a preliminary demonstration of a method for emotion-regulating closed-loop neurostimulation. They further suggest that activity in prefrontal cortex can be used to control a BCI without pre-training on a predicate task. This offers the potential for BCI-based treatments in refractory neurological and mental illness. PMID:24608127

  8. Noradrenergic control of emotion-induced amnesia and hypermnesia.

    PubMed

    Hurlemann, René

    2006-01-01

    Emotional memory encoding is associated with retrograde and anterograde episodic memory changes involving amnesia and hypermnesia, respectively. These effects are noradrenergic-dependent and reflect an interaction with emotional arousal and valence. Whereas anterograde amnesic effects most likely result from attentional capture by emotional arousal, retrograde amnesic and hypermnesic effects may reflect a valence-dependent filter mechanism that operates during emotional memory encoding and controls episodic memory access based upon behavioral significance. This filter mechanism may originnate in amygdala-hippocampal interactions that are modulated by both ascending locus coeruleus and descending prefrontal cortex inputs. PMID:17180877

  9. Genes involved in forebrain development in the zebrafish, Danio rerio.

    PubMed

    Heisenberg, C P; Brand, M; Jiang, Y J; Warga, R M; Beuchle, D; van Eeden, F J; Furutani-Seiki, M; Granato, M; Haffter, P; Hammerschmidt, M; Kane, D A; Kelsh, R N; Mullins, M C; Odenthal, J; Nusslein-Volhard, C

    1996-12-01

    We identified four zebrafish mutants with defects in forebrain induction and patterning during embryogenesis. The four mutants define three genes: masterblind (mbl), silberblick (slb), and knollnase (kas). In mbl embryos, the anterior forebrain acquires posterior forebrain characteristics: anterior structures such as the eyes, olfactory placodes and the telencephalon are missing, whereas the epiphysis located in the posterior forebrain is expanded. In slb embryos, the extension of the embryonic axis is initially delayed and eventually followed by a partial fusion of the eyes. Finally, in kas embryos, separation of the telencephalic primordia is incomplete and dorsal midline cells fail to form a differentiated roof plate. Analysis of the mutant phenotypes indicates that we have identified genes essential for the specification of the anterior forebrain (mbl), positioning of the eyes (slb) and differentiation of the roof plate (kas). In an appendix to this study we list mutants showing alterations in the size of the eyes and abnormal differentiation of the lenses. PMID:9007240

  10. Mirtazapine: an antidepressant with noradrenergic and specific serotonergic effects.

    PubMed

    Stimmel, G L; Dopheide, J A; Stahl, S M

    1997-01-01

    Mirtazapine is a unique antidepressant that refines the specificity of effects on noradrenergic and serotonergic systems. It is an antagonist of presynaptic alpha 2-adrenergic autoreceptors and heteroreceptors on both norepinephrine and serotonin (5-HT) presynaptic axons, plus is a potent antagonist of postsynaptic 5-HT2 and 5-HT3 receptors. The net outcome of these effects is increased noradrenergic activity together with specific increased serotonergic activity, especially at 5-HT1A receptors. This mechanism of action maintains equivalent antidepressant efficacy but minimizes many of the adverse effects common to both tricyclic antidepressants and selective serotonin reuptake inhibitors. Mirtazapine has an onset of clinical effect in 2-4 weeks similar to other antidepressants, although sleep disturbances and anxiety symptoms may improve in the first week of treatment. It has minimal cardiovascular and anticholinergic effects, and essentially lacks serotonergic effects such as gastrointestinal symptoms, insomnia, and sexual dysfunction. Sedation, increased appetite, and weight gain are more common with mirtazapine than with placebo. An elimination half-life of 20-40 hours enables once-daily bedtime dosing. The recommended initial dosage is 15 mg once/day at bedtime, with an effective daily dosage range of 15-45 mg. Cases of overdose of up to 975 mg caused significant sedation but no cardiovascular or respiratory effects or seizures. PMID:9017762

  11. Central stress-integrative circuits: Forebrain glutamatergic and GABAergic projections to the dorsomedial hypothalamus, medial preoptic area, and bed nucleus of the stria terminalis

    PubMed Central

    Myers, Brent; Dolgas, C. Mark; Kasckow, John; Cullinan, William E.; Herman, James P.

    2013-01-01

    Central regulation of hypothalamo-pituitary-adrenocortical (HPA) axis stress responses is mediated by a relatively circumscribed group of projections to the paraventricular hypothalamus (PVN). The dorsomedial hypothalamus (DMH), medial preoptic area (mPOA), and bed nucleus of the stria terminalis (BST) provide direct, predominantly inhibitory, innervation of the PVN. These PVN-projecting neurons are controlled by descending information from limbic forebrain structures, including the prefrontal cortex, amygdala, hippocampus, and septum. The neurochemical phenotype of limbic circuits targeting PVN relays has not been systematically analyzed. The current study combined retrograde tracing and immunohistochemistry/in situ hybridization to identify the specific sites of glutamatergic and GABAergic inputs to the DMH, mPOA, and BST. Following Flouro-Gold (FG) injections in the DMH, retrogradely-labeled cells co-localized with vesicular glutamate transporter mRNA in the prefrontal cortex, ventral hippocampus, and paraventricular thalamus. Co-localization of FG and glutamic acid decarboxylase mRNA was present throughout the central and medial amygdaloid nuclei and septal area. Additionally, the mPOA received predominantly GABAergic input from the septum, amygdala, and BST. The BST received glutamatergic projections from the hippocampus and basomedial amygdala, whereas GABAergic inputs arose from central and medial amygdaloid nuclei. Thus, discrete sets of neurons in the hypothalamus and BST are positioned to summate limbic inputs into PVN regulation and may play a role in HPA dysfunction and stress-related illness. PMID:23661182

  12. Thalamic reticular nucleus in Caiman crocodilus: forebrain connections.

    PubMed

    Pritz, Michael B

    2016-08-01

    Forebrain connections of the thalamic reticular nucleus associated with the lateral forebrain bundle were analyzed in Caiman crocodilus. Both the compact portion, the dorsal peduncular nucleus, and the diffuse part, the perireticular region, associated with the lateral forebrain bundle, were studied. A small tracer injection into the dorsal peduncular nucleus demonstrated reciprocal connections with a restricted portion of the dorsal thalamus. Tracer placements into this nucleus retrogradely labeled cells in a caudal portion of the ventrolateral area of the telencephalon. These results are compared with similar studies in other amniotes. PMID:27233216

  13. Genomic Perspectives of Transcriptional Regulation in Forebrain Development

    PubMed Central

    Nord, Alex S.; Pattabiraman, Kartik; Visel, Axel; Rubenstein, John L. R.

    2015-01-01

    The forebrain is the seat of higher order brain functions, and many human neuropsychiatric disorders are due to genetic defects affecting forebrain development, making it imperative to understand the underlying genetic circuitry. Recent progress now makes it possible to begin fully elucidating the genomic regulatory mechanisms that control forebrain gene expression. Herein, we discuss the current knowledge of how transcription factors drive gene expression programs through their interactions with cis-acting genomic elements, such as enhancers; how analyses of chromatin and DNA modifications provide insights into gene expression states; and how these approaches yield insights into the evolution of the human brain. PMID:25569346

  14. Behavioral models in mice. Implication of the alpha noradrenergic system.

    PubMed

    Hascoët, M; Bourin, M; Bradwejn, J

    1991-01-01

    1. The mechanism of action of drugs might change according to the test used. Several noradrenergic drugs were tested in order to understand their implication in the mobility tests. 2. It was found that clonidine, an Alpha 2 agonist, acted differently according to the test used. It provoked sedation in spontaneous activity test, and anti-immobility effects in the other tests. 3. Tail suspension test is able to show the double acting of clonidine. 4. Idazoxan might act either as an alpha 2 antagonist or as partial alpha 2 agonist. TST shown the unexpected partial alpha agonist effect of the molecule. 5. Forced swimming test is more specific for predicting antidepressant activity than tail suspension test which is close to a spontaneous activity model. PMID:1684874

  15. Nicotine alters limbic function in adolescent rat by a 5-HT1A receptor mechanism.

    PubMed

    Dao, Jasmin M; McQuown, Susan C; Loughlin, Sandra E; Belluzzi, James D; Leslie, Frances M

    2011-06-01

    Epidemiological studies have shown that adolescent smoking is associated with health risk behaviors, including high-risk sexual activity and illicit drug use. Using rat as an animal model, we evaluated the behavioral and biochemical effects of a 4-day, low-dose nicotine pretreatment (60 μg/kg; intravenous) during adolescence and adulthood. Nicotine pretreatment significantly increased initial acquisition of cocaine self-administration, quinpirole-induced locomotor activity, and penile erection in adolescent rats, aged postnatal day (P)32. These effects were long lasting, remaining evident 10 days after the last nicotine treatment, and were observed when nicotine pretreatment was administered during early adolescence (P28-31), but not late adolescence (P38-41) or adulthood (P86-89). Neurochemical analyses of c-fos mRNA expression, and of monoamine transmitter and transporter levels, showed that forebrain limbic systems are continuing to develop during early adolescence, and that this maturation is critically altered by brief nicotine exposure. Nicotine selectively increased c-fos mRNA expression in the nucleus accumbens shell and basolateral amygdala in adolescent, but not adult animals, and altered serotonin markers in these regions as well as the prefrontal cortex. Nicotine enhancement of cocaine self-administration and quinpirole-induced locomotor activity was blocked by co-administration of WAY 100 635 (N-{2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl}-N-(2-pyridinyl)cyclohexanecarboxamide), a selective serotonin 1A (5-HT1A) receptor antagonist. Early adolescent pretreatment with the mixed autoreceptor/heteroceptor 5-HT1A receptor agonist, 8-OH-DPAT, but not the autoreceptor-selective agonist, S-15535, also enhanced quinpirole-induced locomotor activation. Nicotine enhancement of quinpirole-induced penile erection was not blocked by WAY 100 635 nor mimicked by 8-OH-DPAT. These findings indicate that early adolescent nicotine exposure uniquely alters limbic

  16. Common factors among Alzheimer's disease, Parkinson's disease, and epilepsy: possible role of the noradrenergic nervous system.

    PubMed

    Szot, Patricia

    2012-06-01

    The neurodegenerative disorders Alzheimer's disease (AD) and Parkinson's disease (PD) share in common the neuropathologic loss of locus coeruleus (LC) noradrenergic neurons. In addition, these two neurodegenerative disorders share two symptoms that define these disorders: cognitive impairment and depression. The hippocampus is a region that is known to play a role in cognition and depression, and the hippocampus receives sole noradrenergic innervation from LC neurons. However, it is unclear how the loss of LC noradrenergic neurons contributes to these common symptoms in these two disorders. Epilepsy is not considered a neurodegenerative disorder, but the hippocampus is severely affected in temporal lobe epilepsy. Of interest, cognitive impairment and depression are also common comorbid disorders in temporal lobe epilepsy. This article describes common symptoms among these three neurologic disorders and a possible role of the noradrenergic nervous system. PMID:22612810

  17. A review of the adverse effects and safety of noradrenergic antidepressants.

    PubMed

    Whiskey, Eromona; Taylor, David

    2013-08-01

    There are a variety of noradrenergic antidepressants available, most of which act by inhibiting neuronal noradrenaline re-uptake, although few drugs are specific for this action. Where drugs have numerous actions the adverse effects of noradrenaline reuptake may be difficult to isolate, although in this respect the adverse effects of reboxetine, a specific noradrenaline re-uptake inhibitor, are illuminating. Noradrenergic antidepressants typically cause minor changes in blood and heart rate, sweating and insomnia. Other pharmacological actions shown by non-specific antidepressants may act to worsen or mitigate these adverse effects. Noradrenergic drugs are less likely than selective serotonin reuptake inhibitors (SSRIs) to cause sexual dysfunction but more likely to cause urinary hesitancy. Doubts remain over the relative propensity for antidepressants with different modes of action to cause diabetes and hyponatraemia. Noradrenergic actions do not seem to confer a risk of death in overdose. PMID:23784737

  18. The mRNA expression and histological integrity in rat forebrain motor and sensory regions are minimally affected by acrylamide exposure through drinking water

    SciTech Connect

    Bowyer, John F.; Latendresse, John R.; Delongchamp, Robert R.; Warbritton, Alan R.; Thomas, Monzy; Divine, Becky; Doerge, Daniel R.

    2009-11-01

    A study was undertaken to determine whether alterations in the gene expression or overt histological signs of neurotoxicity in selected regions of the forebrain might occur from acrylamide exposure via drinking water. Gene expression at the mRNA level was evaluated by cDNA array and/or RT-PCR analysis in the striatum, substantia nigra and parietal cortex of rat after a 2-week acrylamide exposure. The highest dose tested (maximally tolerated) of approximately 44 mg/kg/day resulted in a significant decreased body weight, sluggishness, and locomotor activity reduction. These physiological effects were not accompanied by prominent changes in gene expression in the forebrain. All the expression changes seen in the 1200 genes that were evaluated in the three brain regions were <= 1.5-fold, and most not significant. Very few, if any, statistically significant changes were seen in mRNA levels of the more than 50 genes directly related to the cholinergic, noradrenergic, GABAergic or glutamatergic neurotransmitter systems in the striatum, substantia nigra or parietal cortex. All the expression changes observed in genes related to dopaminergic function were less than 1.5-fold and not statistically significant and the 5HT1b receptor was the only serotonin-related gene affected. Therefore, gene expression changes were few and modest in basal ganglia and sensory cortex at a time when the behavioral manifestations of acrylamide toxicity had become prominent. No histological evidence of axonal, dendritic or neuronal cell body damage was found in the forebrain due to the acrylamide exposure. As well, microglial activation was not present. These findings are consistent with the absence of expression changes in genes related to changes in neuroinflammation or neurotoxicity. Over all, these data suggest that oral ingestion of acrylamide in drinking water or food, even at maximally tolerable levels, induced neither marked changes in gene expression nor neurotoxicity in the motor and

  19. Mosaic Subventricular Origins of Forebrain Oligodendrogenesis.

    PubMed

    Azim, Kasum; Berninger, Benedikt; Raineteau, Olivier

    2016-01-01

    In the perinatal as well as the adult CNS, the subventricular zone (SVZ) of the forebrain is the largest and most active source of neural stem cells (NSCs) that generates neurons and oligodendrocytes (OLs), the myelin forming cells of the CNS. Recent advances in the field are beginning to shed light regarding SVZ heterogeneity, with the existence of spatially segregated microdomains that are intrinsically biased to generate phenotypically distinct neuronal populations. Although most research has focused on this regionalization in the context of neurogenesis, newer findings underline that this also applies for the genesis of OLs under the control of specific patterning molecules. In this mini review, we discuss the origins as well as the mechanisms that induce and maintain SVZ regionalization. These come in the flavor of specific signaling ligands and subsequent initiation of transcriptional networks that provide a basis for subdividing the SVZ into distinct lineage-specific microdomains. We further emphasize canonical Wnts and FGF2 as essential signaling pathways for the regional genesis of OL progenitors from NSCs of the dorsal SVZ. This aspect of NSC biology, which has so far received little attention, may unveil new avenues for appropriately recruiting NSCs in demyelinating diseases. PMID:27047329

  20. Mosaic Subventricular Origins of Forebrain Oligodendrogenesis

    PubMed Central

    Azim, Kasum; Berninger, Benedikt; Raineteau, Olivier

    2016-01-01

    In the perinatal as well as the adult CNS, the subventricular zone (SVZ) of the forebrain is the largest and most active source of neural stem cells (NSCs) that generates neurons and oligodendrocytes (OLs), the myelin forming cells of the CNS. Recent advances in the field are beginning to shed light regarding SVZ heterogeneity, with the existence of spatially segregated microdomains that are intrinsically biased to generate phenotypically distinct neuronal populations. Although most research has focused on this regionalization in the context of neurogenesis, newer findings underline that this also applies for the genesis of OLs under the control of specific patterning molecules. In this mini review, we discuss the origins as well as the mechanisms that induce and maintain SVZ regionalization. These come in the flavor of specific signaling ligands and subsequent initiation of transcriptional networks that provide a basis for subdividing the SVZ into distinct lineage-specific microdomains. We further emphasize canonical Wnts and FGF2 as essential signaling pathways for the regional genesis of OL progenitors from NSCs of the dorsal SVZ. This aspect of NSC biology, which has so far received little attention, may unveil new avenues for appropriately recruiting NSCs in demyelinating diseases. PMID:27047329

  1. Targeting the Noradrenergic System for Gender-Sensitive Medication Development for Tobacco Dependence

    PubMed Central

    Verplaetse, Terril L.; Weinberger, Andrea H.; Smith, Philip H.; Cosgrove, Kelly P.; Mineur, Yann S.; Picciotto, Marina R.; Mazure, Carolyn M.

    2015-01-01

    Introduction: Tobacco use remains the leading cause of morbidity and mortality for both women and men in the United States, and women often experience poorer smoking cessation outcomes than men. Preliminary evidence suggests there are sex differences in medication effectiveness for smoking cessation. However, current medications do not take into account gender-sensitive treatment development and efficacy, underscoring the importance of this underdeveloped area of research. Methods: We reviewed preclinical and clinical evidence for gender differences in the inability to quit smoking by examining (a) the effect of increased negative affect and stress reactivity on smoking outcomes in women and (b) smoking for nicotine reinforcement in men. We also reviewed the current literature targeting the noradrenergic system as a novel gender-sensitive treatment strategy for tobacco dependence. Results: We hypothesize that noradrenergic agents that normalize noradrenergic activity may differentially attenuate stress reactivity in women and nicotine-related reinforcement in men, indicating that targeting the noradrenergic system for smoking cessation may be effective for both genders, with benefits operating through sex-specific mechanisms. Conclusions: Converging lines of preclinical and clinical evidence suggest that gender-sensitive approaches to medication development for smoking cessation are a critical next step for addressing low quit rates and exacerbated health risks among women. Evidence reviewed indicates that smoking activates different brain systems modulated by noradrenergic activity in women versus men, and noradrenergic compounds may preferentially target these gender-sensitive systems. PMID:25762760

  2. Dynamic Limbic Networks and Social Diversity in Vertebrates: From Neural Context to Neuromodulatory Patterning

    PubMed Central

    Goodson, James L.; Kabelik, David

    2009-01-01

    Vertebrate animals exhibit a spectacular diversity of social behaviors, yet a variety of basic social behavior processes are essential to all species. These include social signaling; discrimination of conspecifics and sexual partners; appetitive and consummatory sexual behaviors; aggression and dominance behaviors; and parental behaviors (the latter with rare exceptions). These behaviors are of fundamental importance and are regulated by an evolutionarily conserved, core social behavior network (SBN) of the limbic forebrain and midbrain. The SBN encodes social information in a highly dynamic, distributed manner, such that behavior is most strongly linked to the pattern of neural activity across the SBN, not the activity of single loci. Thus, shifts in the relative weighting of activity across SBN nodes can conceivably produce almost limitless variation in behavior, including diversity across species (as weighting is modified through evolution), across behavioral contexts (as weights change temporally) and across behavioral phenotypes (as weighting is specified through heritable and developmental processes). Individual neural loci may also express diverse relationships to behavior, depending upon temporal variations in their functional connectivity to other brain regions (“neural context”). We here review the basic properties of the SBN and show how behavioral variation relates to functional connectivity of the network, and discuss ways in which neuroendocrine factors adjust network activity to produce behavioral diversity. In addition to the actions of steroid hormones on SBN state, we examine the temporally plastic and evolutionarily labile properties of the nonapeptides (the vasopressin- and oxytocin-like neuropeptides), and show how variations in nonapeptide signaling within the SBN serve to promote behavioral diversity across social contexts, seasons, phenotypes and species. Although this diversity is daunting in its complexity, the search for common

  3. Evolution of vertebrate forebrain development: how many different mechanisms?

    PubMed Central

    FOLEY, ANN C.; STERN, CLAUDIO D.

    2001-01-01

    Over the past 50 years and more, many models have been proposed to explain how the nervous system is initially induced and how it becomes subdivided into gross regions such as forebrain, midbrain, hindbrain and spinal cord. Among these models is the 2-signal model of Nieuwkoop & Nigtevecht (1954), who suggested that an initial signal (‘activation’) from the organiser both neuralises and specifies the forebrain, while later signals (‘transformation’) from the same region progressively caudalise portions of this initial territory. An opposing idea emerged from the work of Otto Mangold (1933) and other members of the Spemann laboratory: 2 or more distinct organisers, emitting different signals, were proposed to be responsible for inducing the head, trunk and tail regions. Since then, evidence has accumulated that supports one or the other model, but it has been very difficult to distinguish between them. Recently, a considerable body of work from mouse embryos has been interpreted as favouring the latter model, and as suggesting that a ‘head organiser’, required for the induction of the forebrain, is spatially separate from the classic organiser (Hensen's node). An extraembryonic tissue, the ‘anterior visceral endoderm’ (AVE), was proposed to be the source of forebrain-inducing signals. It is difficult to find tissues that are directly equivalent embryologically or functionally to the AVE in other vertebrates, which led some (e.g. Kessel, 1998) to propose that mammals have evolved a new way of patterning the head. We will present evidence from the chick embryo showing that the hypoblast is embryologically and functionally equivalent to the mouse AVE. Like the latter, the hypoblast also plays a role in head development. However, it does not act like a true organiser. It induces pre-neural and pre-forebrain markers, but only transiently. Further development of neural and forebrain phenotypes requires additional signals not provided by the hypoblast. In

  4. Neuropeptide FF receptors as novel targets for limbic seizure attenuation.

    PubMed

    Portelli, Jeanelle; Meurs, Alfred; Bihel, Frederic; Hammoud, Hassan; Schmitt, Martine; De Kock, Joery; Utard, Valerie; Humbert, Jean-Paul; Bertin, Isabelle; Buffel, Ine; Coppens, Jessica; Tourwe, Dirk; Maes, Veronique; De Prins, An; Vanhaecke, Tamara; Massie, Ann; Balasubramaniam, Ambikaipakan; Boon, Paul; Bourguignon, Jean-Jacques; Simonin, Frederic; Smolders, Ilse

    2015-08-01

    Neuropeptide Y (NPY) is a well established anticonvulsant and first-in-class antiepileptic neuropeptide. In this study, the controversial role of NPY1 receptors in epilepsy was reassessed by testing two highly selective NPY1 receptor ligands and a mixed NPY1/NPFF receptor antagonist BIBP3226 in a rat model for limbic seizures. While BIBP3226 significantly attenuated the pilocarpine-induced seizures, neither of the highly selective NPY1 receptor ligands altered the seizure severity. Administration of the NPFF1/NPFF2 receptor antagonist RF9 also significantly attenuated limbic seizure activity. To further prove the involvement of NPFF receptors in these seizure-modulating effects, low and high affinity antagonists for the NPFF receptors were tested. We observed that the low affinity ligand failed to exhibit anticonvulsant properties while the two high affinity ligands significantly attenuated the seizures. Continuous NPFF1 receptor agonist administration also inhibited limbic seizures whereas bolus administration of the NPFF1 receptor agonist was without effect. This suggests that continuous agonist perfusion could result in NPFF1 receptor desensitization and mimic NPFF1 receptor antagonist administration. Our data unveil for the first time the involvement of the NPFF system in the management of limbic seizures. PMID:25963417

  5. Forebrain pathway for auditory space processing in the barn owl.

    PubMed

    Cohen, Y E; Miller, G L; Knudsen, E I

    1998-02-01

    The forebrain plays an important role in many aspects of sound localization behavior. Yet, the forebrain pathway that processes auditory spatial information is not known for any species. Using standard anatomic labeling techniques, we used a "top-down" approach to trace the flow of auditory spatial information from an output area of the forebrain sound localization pathway (the auditory archistriatum, AAr), back through the forebrain, and into the auditory midbrain. Previous work has demonstrated that AAr units are specialized for auditory space processing. The results presented here show that the AAr receives afferent input from Field L both directly and indirectly via the caudolateral neostriatum. Afferent input to Field L originates mainly in the auditory thalamus, nucleus ovoidalis, which, in turn, receives input from the central nucleus of the inferior colliculus. In addition, we confirmed previously reported projections of the AAr to the basal ganglia, the external nucleus of the inferior colliculus (ICX), the deep layers of the optic tectum, and various brain stem nuclei. A series of inactivation experiments demonstrated that the sharp tuning of AAr sites for binaural spatial cues depends on Field L input but not on input from the auditory space map in the midbrain ICX: pharmacological inactivation of Field L eliminated completely auditory responses in the AAr, whereas bilateral ablation of the midbrain ICX had no appreciable effect on AAr responses. We conclude, therefore, that the forebrain sound localization pathway can process auditory spatial information independently of the midbrain localization pathway. PMID:9463450

  6. Lhx2 Regulates the Development of the Forebrain Hem System

    PubMed Central

    Roy, Achira; Gonzalez-Gomez, Miriam; Pierani, Alessandra; Meyer, Gundela; Tole, Shubha

    2014-01-01

    Early brain development is regulated by the coordinated actions of multiple signaling centers at key boundaries between compartments. Three telencephalic midline structures are in a position to play such roles in forebrain patterning: The cortical hem, the septum, and the thalamic eminence at the diencephalic–telencephalic boundary. These structures express unique complements of signaling molecules, and they also produce distinct populations of Cajal–Retzius cells, which are thought to act as “mobile patterning units,” migrating tangentially to cover the telencephalic surface. We show that these 3 structures require the transcription factor Lhx2 to delimit their extent. In the absence of Lhx2 function, all 3 structures are greatly expanded, and the Cajal–Retzius cell population is dramatically increased. We propose that the hem, septum, and thalamic eminence together form a “forebrain hem system” that defines and regulates the formation of the telencephalic midline. Disruptions in the forebrain hem system may be implicated in severe brain malformations such as holoprosencephaly. Lhx2 functions as a central regulator of this system's development. Since all components of the forebrain hem system have been identified across several vertebrate species, the mechanisms that regulate them may have played a fundamental role in driving key aspects of forebrain evolution. PMID:23307637

  7. Norepinephrine deficiency in Parkinson's disease: the case for noradrenergic enhancement.

    PubMed

    Espay, Alberto J; LeWitt, Peter A; Kaufmann, Horacio

    2014-12-01

    The dramatic response of most motor and some nonmotor symptoms to dopaminergic therapies has contributed to maintaining the long-established identity of Parkinson's disease (PD) as primarily a nigrostriatal dopamine (DA) deficiency syndrome. However, DA neurotransmission may be neither the first nor the major neurotransmitter casualty in the neurodegenerative sequence of PD. Growing evidence supports earlier norepinephrine (NE) deficiency resulting from selective degeneration of neurons of the locus coeruleus and sympathetic ganglia. Dopaminergic replacement therapy therefore would seem to neglect some of the motor, behavioral, cognitive, and autonomic impairments that are directly or indirectly associated with the marked deficiency of NE in the brain and elsewhere. Therapeutic strategies to enhance NE neurotransmission have undergone only limited pharmacological testing. Currently, these approaches include selective NE reuptake inhibition, presynaptic α2 -adrenergic receptor blockade, and an NE prodrug, the artificial amino acid L-threo-3,4-dihydroxyphenylserine. In addition to reducing the consequences of deficient noradrenergic signaling, enhancement strate gies have the potential for augmenting the effects of dopaminergic therapies in PD. Furthermore, early recognition of the various clinical manifestations associated with NE deficiency, which may precede development of motor symptoms, could provide a window of opportunity for neuroprotective interventions. PMID:25297066

  8. Noradrenergic Regulation of Glial Activation: Molecular Mechanisms and Therapeutic Implications

    PubMed Central

    Braun, David; Madrigal, Jose L.M; Feinstein, Douglas L

    2014-01-01

    It has been known for many years that the endogenous neurotransmitter noradrenaline (NA) exerts anti-inflammatory and neuroprotective effects both in vitro and in vivo. In many cases the site of action of NA are beta-adrenergic receptors (βARs), causing an increase in intracellular levels of cAMP which initiates a broad cascade of events including suppression of inflammatory transcription factor activities, alterations in nuclear localization of proteins, and induction of patterns of gene expression mediated through activity of the CREB transcription factor. These changes lead not only to reduced inflammatory events, but also contribute to neuroprotective actions of NA by increasing expression of neurotrophic substances including BDNF, GDNF, and NGF. These properties have prompted studies to determine if treatments with drugs to raise CNS NA levels could provide benefit in various neurological conditions and diseases having an inflammatory component. Moreover, increasing evidence shows that disruptions in endogenous NA levels occurs in several diseases and conditions including Alzheimer’s disease (AD), Parkinson’s disease (PD), Down’s syndrome, posttraumatic stress disorder (PTSD), and multiple sclerosis (MS), suggesting that damage to NA producing neurons is a common factor that contributes to the initiation or progression of neuropathology. Methods to increase NA levels, or to reduce damage to noradrenergic neurons, therefore represent potential preventative as well as therapeutic approaches to disease. PMID:25342942

  9. Redefining the Role of Limbic Areas in Cortical Processing.

    PubMed

    Chanes, Lorena; Barrett, Lisa Feldman

    2016-02-01

    There is increasing evidence that the brain actively constructs action and perception using past experience. In this paper, we propose that the direction of information flow along gradients of laminar differentiation provides important insight on the role of limbic cortices in cortical processing. Cortical limbic areas, with a simple laminar structure (e.g., no or rudimentary layer IV), send 'feedback' projections to lower level better laminated areas. We propose that this 'feedback' functions as predictions that drive processing throughout the cerebral cortex. This hypothesis has the potential to provide a unifying framework for an increasing number of proposals that use predictive coding to explain a myriad of neural processes and disorders, and has important implications for hypotheses about consciousness. PMID:26704857

  10. Impaired Autonomic Responses to Emotional Stimuli in Autoimmune Limbic Encephalitis

    PubMed Central

    Schröder, Olga; Schriewer, Elisabeth; Golombeck, Kristin S.; Kürten, Julia; Lohmann, Hubertus; Schwindt, Wolfram; Wiendl, Heinz; Bruchmann, Maximilian; Melzer, Nico; Straube, Thomas

    2015-01-01

    Limbic encephalitis (LE) is an autoimmune-mediated disorder that affects structures of the limbic system, in particular, the amygdala. The amygdala constitutes a brain area substantial for processing of emotional, especially fear-related signals. The amygdala is also involved in neuroendocrine and autonomic functions, including skin conductance responses (SCRs) to emotionally arousing stimuli. This study investigates behavioral and autonomic responses to discrete emotion evoking and neutral film clips in a patient suffering from LE associated with contactin-associated protein-2 (CASPR2) antibodies as compared to a healthy control group. Results show a lack of SCRs in the patient while watching the film clips, with significant differences compared to healthy controls in the case of fear-inducing videos. There was no comparable impairment in behavioral data (emotion report, valence, and arousal ratings). The results point to a defective modulation of sympathetic responses during emotional stimulation in patients with LE, probably due to impaired functioning of the amygdala. PMID:26648907

  11. Task-phase-specific dynamics of basal forebrain neuronal ensembles

    PubMed Central

    Tingley, David; Alexander, Andrew S.; Kolbu, Sean; de Sa, Virginia R.; Chiba, Andrea A.; Nitz, Douglas A.

    2014-01-01

    Cortically projecting basal forebrain neurons play a critical role in learning and attention, and their degeneration accompanies age-related impairments in cognition. Despite the impressive anatomical and cell-type complexity of this system, currently available data suggest that basal forebrain neurons lack complexity in their response fields, with activity primarily reflecting only macro-level brain states such as sleep and wake, onset of relevant stimuli and/or reward obtainment. The current study examined the spiking activity of basal forebrain neuron populations across multiple phases of a selective attention task, addressing, in particular, the issue of complexity in ensemble firing patterns across time. Clustering techniques applied to the full population revealed a large number of distinct categories of task-phase-specific activity patterns. Unique population firing-rate vectors defined each task phase and most categories of task-phase-specific firing had counterparts with opposing firing patterns. An analogous set of task-phase-specific firing patterns was also observed in a population of posterior parietal cortex neurons. Thus, consistent with the known anatomical complexity, basal forebrain population dynamics are capable of differentially modulating their cortical targets according to the unique sets of environmental stimuli, motor requirements, and cognitive processes associated with different task phases. PMID:25309352

  12. Elevated aromatase activity in forebrain synaptic terminals during song

    PubMed Central

    Remage-Healey, Luke; Oyama, Randi K.; Schlinger, Barney A.

    2009-01-01

    The enzyme aromatase (which converts androgens into oestrogens) is expressed throughout the brain in zebra finches. Aromatase is enzymatically active in both cell bodies and synaptic terminals of neurones of the songbird brain, particularly within forebrain motor and auditory networks. Aromatisation within synaptic terminals could thus provide localised and acute modulatory oestrogens within the forebrain during singing and/or audition. In male zebra finches, we tested the hypothesis that forebrain aromatase activity is elevated during singing behaviour and/or hearing male song. This study reports that aromatase activity is elevated in males that were singing for 30 min as compared to non-singing males, and that this elevation occurs only within the cellular compartment that contains synaptic terminals. In a separate experiment, males that heard acoustic playback of song for 30 min exhibited no differences in aromatase activity or in aromatase mRNA levels as revealed by quantitative PCR analysis. Therefore, these results indicate that activation of the motor pathway for song production is linked to local elevations in synaptic aromatase activity within the forebrain of male zebra finches. Future experiments could assess whether elevated synaptic aromatase activity during song is dependent on acute regulation of the aromatase protein. PMID:19207827

  13. Retinoids control anterior and dorsal properties in the developing forebrain.

    PubMed

    Halilagic, Aida; Ribes, Vanessa; Ghyselinck, Norbert B; Zile, Maija H; Dollé, Pascal; Studer, Michèle

    2007-03-01

    We have previously shown that retinoic acid (RA) synthesized by the retinaldehyde dehydrogenase 2 (RALDH2) is required in forebrain development. Deficiency in RA due to inactivation of the mouse Raldh2 gene or to complete absence of retinoids in vitamin-A-deficient (VAD) quails, leads to abnormal morphogenesis of various forebrain derivatives. In this study we show that double Raldh2/Raldh3 mouse mutants have a more severe phenotype in the craniofacial region than single null mutants. In particular, the nasal processes are truncated and the eye abnormalities are exacerbated. It has been previously shown that retinoids act mainly on cell proliferation and survival in the ventral forebrain by regulating SHH and FGF8 signaling. Using the VAD quail model, which survives longer than the Raldh-deficient mouse embryos, we found that retinoids act in maintaining the correct position of anterior and dorsal boundaries in the forebrain by modulating FGF8 anteriorly and WNT signaling dorsally. Furthermore, BMP4 and FGF8 signaling are affected in the nasal region and BMP4 is ventrally expanded in the optic vesicle. At the optic cup stage, Pax6, Tbx5 and Bmp4 are ectopically expressed in the presumptive retinal pigmented epithelium (RPE), while Otx2 and Mitf are not induced, leading to a dorsal transdifferentiation of RPE to neural retina. Therefore, besides being required for survival of ventral structures, retinoids are involved in restricting anterior identity in the telencephalon and dorsal identity in the diencephalon and the retina. PMID:17184764

  14. Laser-scanning photostimulation of optogenetically targeted forebrain circuits.

    PubMed

    Lee, Charles C; Lam, Ying-Wan; Imaizumi, Kazuo; Sherman, S Murray

    2013-01-01

    The sensory forebrain is composed of intricately connected cell types, of which functional properties have yet to be fully elucidated. Understanding the interactions of these forebrain circuits has been aided recently by the development of optogenetic methods for light-mediated modulation of neuronal activity. Here, we describe a protocol for examining the functional organization of forebrain circuits in vitro using laser-scanning photostimulation of channelrhodopsin, expressed optogenetically via viral-mediated transfection. This approach also exploits the utility of cre-lox recombination in transgenic mice to target expression in specific neuronal cell types. Following transfection, neurons are physiologically recorded in slice preparations using whole-cell patch clamp to measure their evoked responses to laser-scanning photostimulation of channelrhodopsin expressing fibers. This approach enables an assessment of functional topography and synaptic properties. Morphological correlates can be obtained by imaging the neuroanatomical expression of channelrhodopsin expressing fibers using confocal microscopy of the live slice or post-fixed tissue. These methods enable functional investigations of forebrain circuits that expand upon more conventional approaches. PMID:24430760

  15. A temperament for learning: The limbic system and myelomeningocele

    PubMed Central

    Vachha, Behroze; Adams, Richard C

    2004-01-01

    This article was the winner of the triennial Casey Holter Memorial Prize awarded by the Society for Research into Hydrocephalus and Spina Bifida, 2004. Abstract This essay explores the link between the limbic/hypothalamic systems within the complex conditions of hydrocephalus and myelomeningocele. Acknowledging the neuroanatomical and neuroendocrine risks inherent in the developing brains of these individuals, we focus on the converging components of temperament, cognition, and language. PMID:15679940

  16. Mephedrone alters basal ganglia and limbic dynorphin systems

    PubMed Central

    German, Christopher L.; Alburges, Mario E.; Hoonakker, Amanda J.; Fleckenstein, Annette E.; Hanson, Glen R.

    2014-01-01

    Mephedrone (4-methymethcathinone) is a synthetic cathinone designer drug that disrupts central nervous system (CNS) dopamine (DA) signaling. Numerous central neuropeptide systems reciprocally interact with dopaminergic neurons to provide regulatory counterbalance, and are altered by aberrant DA activity associated with stimulant exposure. Endogenous opioid neuropeptides are highly concentrated within dopaminergic CNS regions and facilitate many rewarding and aversive properties associated with drug use. Dynorphin, an opioid neuropeptide and kappa receptor agonist, causes dysphoria and aversion to drug consumption through signaling within the basal ganglia and limbic systems, which is affected by stimulants. This study evaluated how mephedrone alters basal ganglia and limbic system dynorphin content, and the role of DA signaling in these changes. Repeated mephedrone administrations (4 × 25 mg/kg/injection, 2-h intervals) selectively increased dynorphin content throughout the dorsal striatum and globus pallidus, decreased dynorphin content within the frontal cortex, and did not alter dynorphin content within most limbic system structures. Pre-treatment with D1-like (SCH-23380) or D2-like (eticlopride) antagonists blocked mephedrone-induced changes in dynorphin content in most regions examined, indicating altered dynorphin activity is a consequence of excessive DA signaling. PMID:25155699

  17. Mephedrone alters basal ganglia and limbic neurotensin systems

    PubMed Central

    German, Christopher L.; Hoonakker, Amanda H.; Fleckenstein, Annette E.; Hanson, Glen R.

    2014-01-01

    Mephedrone (4-methylmethcathinone) is a synthetic cathinone designer drug that alters presynaptic dopamine (DA) activity like many psychostimulants. However, little is known about the postsynaptic dopaminergic impacts of mephedrone. The neuropeptide neurotensin (NT) provides inhibitory feedback for basal ganglia and limbic DA pathways, and postsynaptic D1-like and D2-like receptor activity affects NT tissue levels. This study evaluated how mephedrone alters basal ganglia and limbic system NT content and the role of NT receptor activation in drug consumption behavior. Four 25 mg/kg injections of mephedrone increased NT content in basal ganglia (striatum, substantia nigra and globus pallidus) and the limbic regions (nucleus accumbens core), while a lower dosage (5 mg/kg/injection) only increased striatal NT content. Mephedrone-induced increases in basal ganglia NT levels were mediated by D1-like receptors in the striatum and the substantia nigra by both D1-like and D2-like receptors in the globus pallidus. Mephedrone increased substance P content, another neuropeptide, in the globus pallidus, but not in the dorsal striatum or substantia nigra. Finally, the NT receptor agonist PD149163 blocked mephedrone self-administration, suggesting reduced NT release, as indicated by increased tissue levels, likely contributing to patterns of mephedrone consumption. PMID:24678634

  18. Weight variation before and after surgery in Parkinson's disease: a noradrenergic modulation?

    PubMed

    Guimarães, Joana; Moura, Eduardo; Vieira-Coelho, Maria Augusta; Garrett, Carolina

    2012-08-01

    Changes in the nutritional profile of patients with Parkinson's disease have been reported before and after deep brain stimulation surgery. The major determinants of the weight variation in Parkinson's disease are not yet understood, and the mechanism seems complex. Based on the influence of the sympathetic nervous system in metabolic syndrome obesity, the intent of the present review is to consider the role of noradrenergic modulation on weight variations in Parkinson's disease. In this review the authors raise the following hypothesis: weight variation in Parkinson's disease before and after deep brain stimulation of the subthalamic nucleus could be influenced by noradrenergic interaction between the locus coeruleus, subthalamic nucleus, and hypothalamic nucleus. PMID:22700383

  19. Intracranial Metastatic Disease Spares the Limbic Circuit: A Review of 697 Metastatic Lesions in 107 Patients

    SciTech Connect

    Marsh, James C.; Herskovic, Arnold M.; Gielda, Benjamin T.; Hughes, Frank F.; Hoeppner, Thomas; Turian, Julius; Abrams, Ross A.

    2010-02-01

    Purpose: We report the incidence of metastatic involvement of the limbic circuit in a retrospective review of patients treated at our institution. This review was performed to assess the feasibility of selectively sparing the limbic system during whole-brain radiotherapy and prophylactic cranial irradiation. Methods and Materials: We identified 697 intracranial metastases in 107 patients after reviewing contrast-enhanced CT and/or MR image sets for each patient. Lesions were localized to the limbic circuit or to the rest of the brain/brain stem. Patients were categorized by tumor histology (e.g., non-small-cell lung cancer, small-cell lung cancer, breast cancer, and other) and by total number of intracranial metastases (1-3, oligometastatic; 4 or more, nonoligometastatic). Results: Thirty-six limbic metastases (5.2% of all metastases) were identified in 22 patients who had a median of 16.5 metastases/patient (limbic metastases accounted for 9.9% of their lesions). Sixteen metastases (2.29%) involved the hippocampus, and 20 (2.86%) involved the rest of the limbic circuit; 86.2% of limbic metastases occurred in nonoligometastatic patients, and 13.8% occurred in oligometastatic patients. The incidence of limbic metastases by histologic subtype was similar. The incidence of limbic metastases in oligometastatic patients was 4.9% (5/103): 0.97%, hippocampus; 3.9%, remainder of the limbic circuit. One of 53 oligometastatic patients (1.9%) had hippocampal metastases, while 4/53 (7.5%) had other limbic metastases. Conclusions: Metastatic involvement of the limbic circuit is uncommon and limited primarily to patients with nonoligometastatic disease, supporting our hypothesis that it is reasonable to selectively exclude or reduce the dose to the limbic circuit when treating patients with prophylactic cranial irradiation or whole-brain radiotherapy for oligometastatic disease not involving these structures.

  20. Facilitation of Learning by Social-Emotional Feedback in Humans Is Beta-Noradrenergic-Dependent

    ERIC Educational Resources Information Center

    Mihov, Yoan; Mayer, Simon; Musshoff, Frank; Maier, Wolfgang; Kendrick, Keith M.; Hurlemann, Rene

    2010-01-01

    Adaptive behavior in dynamic environments critically depends on the ability to learn rapidly and flexibly from the outcomes of prior choices. In social environments, facial expressions of emotion often serve as performance feedback and thereby guide declarative learning. Abundant evidence implicates beta-noradrenergic signaling in the modulatory…

  1. The Memory Function of Noradrenergic Activity in Non-REM Sleep

    ERIC Educational Resources Information Center

    Gais, Steffen; Rasch, Bjorn; Dahmen, Johannes C.; Sara, Susan; Born, Jan

    2011-01-01

    There is a long-standing assumption that low noradrenergic activity during sleep reflects mainly the low arousal during this brain state. Nevertheless, recent research has demonstrated that the locus coeruleus, which is the main source of cortical noradrenaline, displays discrete periods of intense firing during non-REM sleep, without any signs of…

  2. Noradrenergic Action in Prefrontal Cortex in the Late Stage of Memory Consolidation

    ERIC Educational Resources Information Center

    Tronel, Sophie; Feenstra, Matthijs G. P.; Sara, Susan J.

    2004-01-01

    These experiments investigated the role of the noradrenergic system in the late stage of memory consolidation and in particular its action at beta receptors in the prelimbic region (PL) of the prefrontal cortex in the hours after training. Rats were trained in a rapidly acquired, appetitively motivated foraging task based on olfactory…

  3. Noradrenergic Control of Odor Recognition in a Nonassociative Olfactory Learning Task in the Mouse

    ERIC Educational Resources Information Center

    Veyrac, Alexandra; Nguyen, Veronique; Marien, Marc; Didier, Anne; Jourdan, Francois

    2007-01-01

    The present study examined the influence of pharmacological modulations of the locus coeruleus noradrenergic system on odor recognition in the mouse. Mice exposed to a nonrewarded olfactory stimulation (training) were able to memorize this odor and to discriminate it from a new odor in a recall test performed 15 min later. At longer delays (30 or…

  4. Orphanin FQ/Nociceptin Interacts with the Basolateral Amygdala Noradrenergic System in Memory Consolidation

    ERIC Educational Resources Information Center

    Roozendaal, Benno; Lengvilas, Ray; McGaugh, James L.; Civelli, Olivier; Reinscheid, Rainer K.

    2007-01-01

    Extensive evidence indicates that the basolateral complex of the amygdala (BLA) mediates hormonal and neurotransmitter effects on the consolidation of emotionally influenced memory and that such modulatory influences involve noradrenergic activation of the BLA. As the BLA also expresses a high density of receptors for orphanin FQ/nociceptin…

  5. Acute nonparaneoplastic limbic encephalitis in childhood: a case series in Japan.

    PubMed

    Sakuma, Hiroshi; Sugai, Kenji; Sasaki, Masayuki

    2010-09-01

    Limbic encephalitis not associated with malignancy was investigated in Japanese children, with particular focus on clinical features distinct from adult cases. Clinical, laboratory, and radiographic findings were studied in pediatric nonparaneoplastic limbic encephalitis, based on a literature review and questionnaire-based analyses. Analysis of 14 cases revealed the predominance of seizure occurrence, disturbance in consciousness, and frequent extralimbic signs. The majority manifested antecedent febrile illnesses, suggesting the involvement of infection-induced autoimmunity targeted to neuronal antigens. These clinical observations indicate a child-specific phenotype of limbic encephalitis. Further studies on its immunopathogenesis are needed to determine whether childhood limbic encephalitis is a distinct subcategory. PMID:20691937

  6. The noradrenergic paradox: implications in the management of depression and anxiety.

    PubMed

    Montoya, Alonso; Bruins, Robert; Katzman, Martin A; Blier, Pierre

    2016-01-01

    Both major depressive disorder and the anxiety disorders are major causes of disability and markedly contribute to a significant global burden of the disease worldwide. In part because of the significant socioeconomic burden associated with these disorders, theories have been developed to specifically build clinical treatment approaches. One such theory, the monoaminergic hypothesis, has led to the development of several generations of selective and nonselective inhibitors of transporters of serotonin and norepinephrine, with the goal of augmenting monoaminergic transmission. These efforts have led to considerable success in the development of antidepressant therapeutics. However, there is a strong correlation between enhanced noradrenergic activity and fear and anxiety. Consequently, some physicians have expressed concerns that the same enhanced noradrenergic activity that alleviates depression could also promote anxiety. The fact that the serotonergic and noradrenergic reuptake inhibitors are successfully used in the treatment of anxiety and panic disorders seems paradoxical. This review was undertaken to determine if any clinical evidence exists to show that serotonergic and noradrenergic reuptake inhibitors can cause anxiety. The PubMed, EMBASE, and Cochrane Library databases were searched, and the results limited to randomized, double-blind, placebo-controlled studies performed in nongeriatric adults and with clear outcome measures were reported. Based on these criteria, a total of 52 studies were examined. Patients in these studies suffered from depression or anxiety disorders (generalized and social anxiety disorders, panic disorder, and posttraumatic stress disorder). The large majority of these studies employed venlafaxine or duloxetine, and the remainder used tri-cyclic antidepressants, atomoxetine, or reboxetine. All the studies reported clinically significant alleviation of depressive and/or anxious symptoms by these therapeutics. In none of these

  7. HoxB8 in noradrenergic specification and differentiation of the autonomic nervous system.

    PubMed

    Huber, Leslie; Ferdin, Marius; Holzmann, Julia; Stubbusch, Jutta; Rohrer, Hermann

    2012-03-01

    Different prespecification of mesencephalic and trunk neural crest cells determines their response to environmental differentiation signals and contributes to the generation of different autonomic neuron subtypes, parasympathetic ciliary neurons in the head and trunk noradrenergic sympathetic neurons. The differentiation of ciliary and sympathetic neurons shares many features, including the initial BMP-induced expression of noradrenergic characteristics that is, however, subsequently lost in ciliary but maintained in sympathetic neurons. The molecular basis of specific prespecification and differentiation patterns has remained unclear. We show here that HoxB gene expression in trunk neural crest is maintained in sympathetic neurons. Ectopic expression of a single HoxB gene, HoxB8, in mesencephalic neural crest results in a strongly increased expression of sympathetic neuron characteristics like the transcription factor Hand2, tyrosine hydroxylase (TH) and dopamine-beta-hydroxylase (DBH) in ciliary neurons. Other subtype-specific properties like RGS4 and RCad are not induced. HoxB8 has only minor effects in postmitotic ciliary neurons and is unable to induce TH and DBH in the enteric nervous system. Thus, we conclude that HoxB8 acts by maintaining noradrenergic properties transiently expressed in ciliary neuron progenitors during normal development. HoxC8, HoxB9, HoxB1 and HoxD10 elicit either small and transient or no effects on noradrenergic differentiation, suggesting a selective effect of HoxB8. These results implicate that Hox genes contribute to the differential development of autonomic neuron precursors by maintaining noradrenergic properties in the trunk sympathetic neuron lineage. PMID:22236961

  8. The noradrenergic paradox: implications in the management of depression and anxiety

    PubMed Central

    Montoya, Alonso; Bruins, Robert; Katzman, Martin A; Blier, Pierre

    2016-01-01

    Both major depressive disorder and the anxiety disorders are major causes of disability and markedly contribute to a significant global burden of the disease worldwide. In part because of the significant socioeconomic burden associated with these disorders, theories have been developed to specifically build clinical treatment approaches. One such theory, the monoaminergic hypothesis, has led to the development of several generations of selective and nonselective inhibitors of transporters of serotonin and norepinephrine, with the goal of augmenting monoaminergic transmission. These efforts have led to considerable success in the development of antidepressant therapeutics. However, there is a strong correlation between enhanced noradrenergic activity and fear and anxiety. Consequently, some physicians have expressed concerns that the same enhanced noradrenergic activity that alleviates depression could also promote anxiety. The fact that the serotonergic and noradrenergic reuptake inhibitors are successfully used in the treatment of anxiety and panic disorders seems paradoxical. This review was undertaken to determine if any clinical evidence exists to show that serotonergic and noradrenergic reuptake inhibitors can cause anxiety. The PubMed, EMBASE, and Cochrane Library databases were searched, and the results limited to randomized, double-blind, placebo-controlled studies performed in nongeriatric adults and with clear outcome measures were reported. Based on these criteria, a total of 52 studies were examined. Patients in these studies suffered from depression or anxiety disorders (generalized and social anxiety disorders, panic disorder, and posttraumatic stress disorder). The large majority of these studies employed venlafaxine or duloxetine, and the remainder used tri-cyclic antidepressants, atomoxetine, or reboxetine. All the studies reported clinically significant alleviation of depressive and/or anxious symptoms by these therapeutics. In none of these

  9. Evidence for evolutionary specialization in human limbic structures

    PubMed Central

    Barger, Nicole; Hanson, Kari L.; Teffer, Kate; Schenker-Ahmed, Natalie M.; Semendeferi, Katerina

    2014-01-01

    Increasingly, functional and evolutionary research has highlighted the important contribution emotion processing makes to complex human social cognition. As such, it may be asked whether neural structures involved in emotion processing, commonly referred to as limbic structures, have been impacted in human brain evolution. To address this question, we performed an extensive evolutionary analysis of multiple limbic structures using modern phylogenetic tools. For this analysis, we combined new volumetric data for the hominoid (human and ape) amygdala and 4 amygdaloid nuclei, hippocampus, and striatum, collected using stereological methods in complete histological series, with previously published datasets on the amygdala, orbital and medial frontal cortex, and insula, as well as a non-limbic structure, the dorsal frontal cortex, for contrast. We performed a parallel analysis using large published datasets including many anthropoid species (human, ape, and monkey), but fewer hominoids, for the amygdala and 2 amygdaloid subdivisions, hippocampus, schizocortex, striatum, and septal nuclei. To address evolutionary change, we compared observed human values to values predicted from regressions run through (a) non-human hominoids and (b) non-human anthropoids, assessing phylogenetic influence using phylogenetic generalized least squares regression. Compared with other hominoids, the volumes of the hippocampus, the lateral nucleus of the amygdala, and the orbital frontal cortex were, respectively, 50, 37, and 11% greater in humans than predicted for an ape of human hemisphere volume, while the medial and dorsal frontal cortex were, respectively, 26 and 29% significantly smaller. Compared with other anthropoids, only human values for the striatum fell significantly below predicted values. Overall, the data present support for the idea that regions involved in emotion processing are not necessarily conserved or regressive, but may even be enhanced in recent human evolution

  10. Basal forebrain control of wakefulness and cortical rhythms

    PubMed Central

    Anaclet, Christelle; Pedersen, Nigel P.; Ferrari, Loris L.; Venner, Anne; Bass, Caroline E.; Arrigoni, Elda; Fuller, Patrick M.

    2015-01-01

    Wakefulness, along with fast cortical rhythms and associated cognition, depend on the basal forebrain (BF). BF cholinergic cell loss in dementia and the sedative effect of anti-cholinergic drugs have long implicated these neurons as important for cognition and wakefulness. The BF also contains intermingled inhibitory GABAergic and excitatory glutamatergic cell groups whose exact neurobiological roles are unclear. Here we show that genetically targeted chemogenetic activation of BF cholinergic or glutamatergic neurons in behaving mice produced significant effects on state consolidation and/or the electroencephalogram but had no effect on total wake. Similar activation of BF GABAergic neurons produced sustained wakefulness and high-frequency cortical rhythms, whereas chemogenetic inhibition increased sleep. Our findings reveal a major contribution of BF GABAergic neurons to wakefulness and the fast cortical rhythms associated with cognition. These findings may be clinically applicable to manipulations aimed at increasing forebrain activation in dementia and the minimally conscious state. PMID:26524973

  11. Basal forebrain control of wakefulness and cortical rhythms.

    PubMed

    Anaclet, Christelle; Pedersen, Nigel P; Ferrari, Loris L; Venner, Anne; Bass, Caroline E; Arrigoni, Elda; Fuller, Patrick M

    2015-01-01

    Wakefulness, along with fast cortical rhythms and associated cognition, depend on the basal forebrain (BF). BF cholinergic cell loss in dementia and the sedative effect of anti-cholinergic drugs have long implicated these neurons as important for cognition and wakefulness. The BF also contains intermingled inhibitory GABAergic and excitatory glutamatergic cell groups whose exact neurobiological roles are unclear. Here we show that genetically targeted chemogenetic activation of BF cholinergic or glutamatergic neurons in behaving mice produced significant effects on state consolidation and/or the electroencephalogram but had no effect on total wake. Similar activation of BF GABAergic neurons produced sustained wakefulness and high-frequency cortical rhythms, whereas chemogenetic inhibition increased sleep. Our findings reveal a major contribution of BF GABAergic neurons to wakefulness and the fast cortical rhythms associated with cognition. These findings may be clinically applicable to manipulations aimed at increasing forebrain activation in dementia and the minimally conscious state. PMID:26524973

  12. Brainstem and limbic encephalitis with paraneoplastic neuromyelitis optica.

    PubMed

    Moussawi, Khaled; Lin, David J; Matiello, Marcelo; Chew, Sheena; Morganstern, Daniel; Vaitkevicius, Henrikas

    2016-01-01

    The spectrum of disorders associated with anti-neuromyelitis optica (NMO) antibody is being extended to include infrequent instances associated with cancer. We describe a patient with brainstem and limbic encephalitis from NMO-immunoglobulin G in serum and cerebrospinal fluid in the context of newly diagnosed breast cancer. The neurological features markedly improved with excision of her breast cancer and immune suppressive therapy. This case further broadens the NMO spectrum disorders (NMOSD) by an association between NMOSD and cancer and raises the question of coincidental occurrence and the appropriate circumstances to search for a tumor in certain instances of NMO. PMID:26412254

  13. Mast cells in the sheep, hedgehog and rat forebrain

    PubMed Central

    MICHALOUDI, HELEN C.; PAPADOPOULOS, GEORGIOS C.

    1999-01-01

    The study was designed to reveal the distribution of various mast cell types in the forebrain of the adult sheep, hedgehog and rat. Based on their histochemical and immunocytochemical characteristics, mast cells were categorised as (1) connective tissue-type mast cells, staining metachromatically purple with the toluidine blue method, or pale red with the Alcian blue/safranin method, (2) mucosal-type or immature mast cells staining blue with the Alcian blue/safranin method and (3) serotonin immunopositive mast cells. All 3 types of brain mast cells in all species studied were located in both white and grey matter, often associated with intraparenchymal blood vessels. Their distribution pattern exhibited interspecies differences, while their number varied considerably not only between species but also between individuals of each species. A distributional left-right asymmetry, with more cells present on the left side, was observed in all species studied but it was most prominent in the sheep brain. In the sheep, mast cells were abundantly distributed in forebrain areas, while in the hedgehog and the rat forebrain, mast cells were less widely distributed and were relatively or substantially fewer in number respectively. A limited number of brain mast cells, in all 3 species, but primarily in the rat, were found to react both immunocytochemically to 5-HT antibody and histochemically with Alcian blue/safranin staining. PMID:10634696

  14. Effects of noradrenergic denervation by anti-DBH-saporin on behavioral responsivity to L-DOPA in the hemi-parkinsonian rat.

    PubMed

    Ostock, Corinne Y; Lindenbach, David; Goldenberg, Adam A; Kampton, Elias; Bishop, Christopher

    2014-08-15

    Dopamine (DA) replacement with l-DOPA remains the most effective pharmacotherapy for motor symptoms of Parkinson's disease (PD) including tremor, postural instability, akinesia, and bradykinesia. Prolonged L-DOPA use frequently leads to deleterious side effects including involuntary choreic and dystonic movements known as L-DOPA induced dyskinesias (LID). DA loss in PD is frequently accompanied by concomitant noradrenergic (NE) denervation of the locus coeruleus (LC); however, the effects of NE loss on L-DOPA efficacy and LID remain controversial and are often overlooked in traditional animal models of PD. The current investigation examined the role of NE loss in L-DOPA therapy by employing the NE specific neurotoxin anti-DA-beta hydroxylase saporin (αDBH) in a rat model of PD. Rats received unilateral 6-hydroxydopamine lesions of the medial forebrain bundle to deplete nigral DA and intraventricular injection of vehicle (DA lesioned rats) or αDBH (DANE lesioned rats) to destroy NE neurons bilaterally. Results indicated that αDBH infusion drastically reduced NE neuron markers within the LC compared to rats that received vehicle treatment. Behaviorally, this loss did not alter the development or expression of L-DOPA- or DA agonist-induced dyskinesia. However, rats with additional NE lesions were less responsive to L-DOPA's pro-motor effects. Indeed, DANE lesioned animals rotated less and showed less attenuation of parkinsonian stepping deficits following high doses of L-DOPA than DA lesioned animals. These findings suggest that severe NE loss may reduce L-DOPA treatment efficacy and demonstrate that degradation of the NE system is an important consideration when evaluating L-DOPA effects in later stage PD. PMID:24837745

  15. The Subthalamic Nucleus, Limbic Function, and Impulse Control.

    PubMed

    Rossi, P Justin; Gunduz, Aysegul; Okun, Michael S

    2015-12-01

    It has been well documented that deep brain stimulation (DBS) of the subthalamic nucleus (STN) to address some of the disabling motor symptoms of Parkinson's disease (PD) can evoke unintended effects, especially on non-motor behavior. This observation has catalyzed more than a decade of research concentrated on establishing trends and identifying potential mechanisms for these non-motor effects. While many issues remain unresolved, the collective result of many research studies and clinical observations has been a general recognition of the role of the STN in mediating limbic function. In particular, the STN has been implicated in impulse control and the related construct of valence processing. A better understanding of STN involvement in these phenomena could have important implications for treating impulse control disorders (ICDs). ICDs affect up to 40% of PD patients on dopamine agonist therapy and approximately 15% of PD patients overall. ICDs have been reported to be associated with STN DBS. In this paper we will focus on impulse control and review pre-clinical, clinical, behavioral, imaging, and electrophysiological studies pertaining to the limbic function of the STN. PMID:26577509

  16. Projections from the parabrachial nucleus to the vestibular nuclei: potential substrates for autonomic and limbic influences on vestibular responses.

    PubMed

    Balaban, Carey D

    2004-01-16

    Previous anatomical studies in rabbits and rats have shown that the superior vestibular nucleus (SVN), medial vestibular nucleus (MVN) and inferior vestibular nucleus (IVN) project to the parabrachial nucleus (PBN) and Kölliker-Fuse (KF) nucleus. Adult male albino rabbits and Long-Evans rats received iontophoretic injections of biotinylated dextran amine, Phaseolus vulgaris leucoagglutinin, Fluoro-Gold or tetramethylrhodamine dextran amine into either the vestibular nuclei or the PBN and KF nuclei. The results were similar in both rats and rabbits. Injections of retrograde tracers into the vestibular nuclei produced retrogradely labeled neurons bilaterally in caudal third of the medial, external medial, and external lateral PBN in both species, with more variable labeling in KF. Rats also had consistent bilateral (predominantly contralateral) labeling in the ventrolateral PBN. The most prominent labeling was produced from injections that included the SVN, with fewer labeled neurons observed from injections in the caudal MVN and the IVN. Anterograde transport of BDA from injections into the PBN and KF nuclei of rabbits revealed prominent projections to the SVN, dorsal aspect of the rostral MVN, caudal MVN, pars beta of the LVN and IVN. These connections appear to contain a component that is reciprocal to the vestibulo-parabrachial pathway and a non-reciprocal component to regions connected with the vestibulocerebellum and vestibulo-motor reflex pathways. These connections support the concept that a synthesis of autonomic, vestibular and limbic information is an integral property of pathways related to balance control in both the brain stem and forebrain. It is suggested that these projections may contribute broadly to both performance tradeoffs in vestibular-related pathways during variations in the behavioral context and affective state and the close association between anxiety and balance function. PMID:14670639

  17. Electroencephalographic Evaluation for Early Diagnosis of Limbic Encephalitis.

    PubMed

    Pessa, Maria Elena; Janes, Francesco; Gigli, Gian Luigi

    2016-07-01

    Limbic encephalitis (LE) is an inflammation of structures of limbic system. It may be an autoimmune disease or secondary to a neoplasia. Onset is subacute within a few weeks and clinical presentation is characterized by behavioral changes, psychiatric symptoms, short-term memory loss, and epileptic seizures. Diagnosis is typically set after a magnetic resonance imaging (MRI) scan, revealing hyperintensity in limbic structures on T2, fluid-attenuated inversion recovery (FLAIR), and diffusion-weighted imaging (DWI) sequences or detection of antineuronal antibodies; EEG aspecific alterations on temporal areas usually match with MRI and laboratory findings. Specific diagnostic criteria are still under debate. We describe a case presenting with EEG alterations before MRI ones.A 36-year-old woman came to our attention for a first generalized tonic-clonic seizure, several episodes of likely epigastric auras and memory loss. Her clinical history was unremarkable. Neurological examination and brain MRI with gadolinium were normal. Electroencephalographic (EEG) recordings showed theta activity and sharp elements in frontotemporal regions. Therapy with levetiracetam 1000 mg/day was started, but she had another generalized seizure and episodes of epigastric auras increased to 10 per day. After 2 months, another cerebral MRI revealed areas of swelling and signal alteration in deep left temporal areas, especially in hippocampal and parahippocampal gyrus. A spectroscopic evaluation revealed decreased N-acetyl aspartate peak and increased choline and myo-inositol peaks in left frontotemporal areas. These findings were consistent with LE. Cerebrospinal fluid (CSF) analysis was normal; viral serology and onconeuronal antibodies on CSF and blood were negative. Patient was treated with high-dosage steroids, with improvement in memory, epileptic seizures and auras. A third MRI revealed no signal alterations.In conclusion, the clinical picture initially did not meet accepted diagnostic

  18. Noradrenergic blockade stabilizes prefrontal activity and enables fear extinction under stress

    PubMed Central

    Fitzgerald, Paul J.; Giustino, Thomas F.; Seemann, Jocelyn R.; Maren, Stephen

    2015-01-01

    Stress-induced impairments in extinction learning are believed to sustain posttraumatic stress disorder (PTSD). Noradrenergic signaling may contribute to extinction impairments by modulating medial prefrontal cortex (mPFC) circuits involved in fear regulation. Here we demonstrate that aversive fear conditioning rapidly and persistently alters spontaneous single-unit activity in the prelimbic and infralimbic subdivisions of the mPFC in behaving rats. These conditioning-induced changes in mPFC firing were mitigated by systemic administration of propranolol (10 mg/kg, i.p.), a β-noradrenergic receptor antagonist. Moreover, propranolol administration dampened the stress-induced impairment in extinction observed when extinction training is delivered shortly after fear conditioning. These findings suggest that β-adrenoceptors mediate stress-induced changes in mPFC spike firing that contribute to extinction impairments. Propranolol may be a helpful adjunct to behavioral therapy for PTSD, particularly in patients who have recently experienced trauma. PMID:26124100

  19. Noradrenergic lesioning with an anti-dopamine beta-hydroxylase immunotoxin

    NASA Technical Reports Server (NTRS)

    Picklo, M. J.; Wiley, R. G.; Lappi, D. A.; Robertson, D.

    1994-01-01

    Sympathectomy has been achieved by a variety of methods but each has its limitations. These include lack of tissue specificity, incomplete lesioning, and the age range of susceptibility to the lesioning. To circumvent these drawbacks, an immunotoxin was constructed using a monoclonal antibody against the noradrenergic specific enzyme dopamine beta-hydroxylase (D beta H) coupled via a disulfide bond to saporin, a ribosomal inactivating protein. Three days after intravenous injection of the anti-D beta H immunotoxin (50 micrograms) into adult Sprague-Dawley rats, 66% of neurons in the superior cervical ganglia were chromatolytic. Superior cervical ganglia neurons were poisoned in 1 day old and 1 week old (86% of neurons) neonatal rats following subcutaneous injection of 3.75 and 15 micrograms, respectively. The anti-D beta H immunotoxin will be a useful tool in the study of the peripheral noradrenergic system in adult and neonatal animals.

  20. Sympathetic noradrenergic before striatal dopaminergic denervation: relevance to Braak staging of synucleinopathy

    PubMed Central

    Goldstein, David S.; Holmes, Courtney; Sewell, LaToya; Park, Mee Yeong; Sharabi, Yehonatan

    2016-01-01

    Braak's staging concept of Lewy body disease pathogenesis is based on a spatiotemporal sequence of alpha-synuclein deposition, with autonomic nervous system involvement before synucleinopathy in substantia nigra neurons. A patient with primary chronic autonomic failure underwent biennial brain 6-[18F]DOPA and myocardial 6-[18F]dopamine scanning over 4 years. Low myocardial radioactivity indicated cardiac noradrenergic denervation that persisted. Striatal 6-[18F]DOPA-derived radioactivity initially was normal, 2 years later was decreased subtly, and by 4 years was clearly decreased, accompanied by dementia and parkinsonism. In this case, neuroimaging evidence of cardiac noradrenergic denervation and subsequent progressive striatal dopaminergic denervation fit with Braak staging. PMID:21796351

  1. Laminar-selective noradrenergic and serotoninergic modulation includes spinoparabrachial cells after inflammation.

    PubMed

    Wei, F; Dubner, R; Ren, K

    1999-06-01

    We evaluated the effects of chemical lesions on hindpaw inflammation-induced Fos protein expression in spinoparabrachial neurons that were retrogradely labeled by Fluoro-Gold. The descending serotoninergic and noradrenergic pathways were destroyed by the selective neurotoxins, 5,7-DHT and DSP-4, respectively. After 5,7-DHT treatment there was a significant increase in double-labeled neurons only in the lateral reticulated neck of the dorsal horn 24h after inflammation compared with vehicle-injected controls. In contrast, the DSP-4 treatment resulted in a more robust increase in double-labeled neurons in the ipsilateral superficial dorsal horn than in the neck of the dorsal horn. These results indicate that after inflammation the enhanced modulation from descending serotoninergic and noradrenergic pathways targets supraspinally projecting neurons to dampen increased ascending nociceptive input. Further, these pathways differentially suppress the responses of spinoparabrachial neurons in the deep and superficial dorsal horn. PMID:10501570

  2. Reduced response to chronic mild stress in PACAP mutant mice is associated with blunted FosB expression in limbic forebrain and brainstem centers.

    PubMed

    Kormos, Viktória; Gáspár, László; Kovács, László Á; Farkas, József; Gaszner, Tamás; Csernus, Valér; Balogh, András; Hashimoto, Hitoshi; Reglődi, Dóra; Helyes, Zsuzsanna; Gaszner, Balázs

    2016-08-25

    Pituitary adenylate cyclase-activating polypeptide (PACAP) has been implicated in stress adaptation with potential relevance in mood disorder management. PACAP deficient (KO) mice on CD1 background were shown to have depression-like phenotype. Here we aimed at investigating effects of chronic variable mild stress (CVMS) in non-injected, vehicle and imipramine-treated KO mice vs. wildtype (WT) counterparts. We hypothesized reduced FosB neuronal activity in stress-related centers, altered activity and peptide/neurotransmitter content of corticotropin-releasing factor (CRF) cells of the oval (ovBST) bed nucleus of stria terminalis (BST), urocortin 1 (Ucn1) neurons of centrally projecting Edinger-Westphal nucleus (cpEW) and serotonin (5HT) cells of dorsal raphe (DR) in PACAP deficiency. CVMS caused decreased body weight and increased adrenal size, corticosterone (CORT) titers and depression-like behavior in WT mice, in contrast to KO animals. CVMS increased FosB in the central (CeA) and medial amygdala, dorsomedial (dmBST), ventral (vBST), ovBST, CA1 area, dentate gyrus (DG), ventral lateral septum, parvo- (pPVN) and magnocellular paraventricular nucleus, lateral periaqueductal gray, cpEW and DR. Lack of PACAP blunted the CVMS-induced FosB rise in the CeA, ovBST, dmBST, vBST, CA1 area, pPVN and DR. The CVMS-induced FosB expression in ovBST-CRF and cpEW-Ucn1 neurons was abolished in KO mice. Although CVMS did not induce FosB in 5HT-DR neurons, PACAP KO mice had increased 5HT cell counts and 5HT content. We conclude that PACAP deficiency affects neuronal reactivity in a brain area-specific manner in stress centers, as well as in ovBST-CRF, cpEW-Ucn1 and 5HT-DR neurons leading to reduced CVMS response and altered depression level. PMID:27282087

  3. Excitation of locus coeruleus noradrenergic neurons by thyrotropin-releasing hormone.

    PubMed

    Ishibashi, Hitoshi; Nakahata, Yoshihisa; Eto, Kei; Nabekura, Junichi

    2009-12-01

    Locus coeruleus (LC) noradrenergic neurons are implicated in a variety of functions including the regulation of vigilance and the modulation of sensory processing. Thyrotropin-releasing hormone (TRH) is an endogenous neuropeptide that induces a variety of behavioural changes including arousal and antinociception. In the present study, we explored whether the activity of LC noradrenergic neurons is modulated by TRH. Using current-clamp recording from isolated rat LC neurons, we found that TRH increased the firing rate of spontaneous action potentials. The TRH action was mimicked by TRH analogues including taltirelin and TRH-gly. In voltage-clamp recording at a holding potential of 50 mV, TRH produced an inward current associated with a decrease in the membrane K+ conductance. This current was inhibited by the TRH receptor antagonist chlordiazepoxide. Following inhibition of the pH-sensitive K+ conductance by extracellular acidification, the TRH response was fully inhibited. The TRH-induced current was also inhibited by the phospholipase C (PLC) inhibitor U-73122, but not by the protein kinase C inhibitor chelerythrine nor by chelation of intracellular Ca2+ by BAPTA. The recovery from the facilitatory action of TRH on the spike frequency was markedly inhibited by a high concentration of wortmannin. These results suggest that TRH activates LC noradrenergic neurons by decreasing an acid-sensitive K+ conductance via PLC-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate. The present findings demonstrate that TRH activates LC neurons and characterize the underlying signalling mechanisms. The action of TRH on LC neurons may influence a variety of CNS functions related to the noradrenergic system which include arousal and analgesia. PMID:19840999

  4. Organization of medullary adrenergic and noradrenergic projections to the periaqueductal gray matter in the rat.

    PubMed

    Herbert, H; Saper, C B

    1992-01-01

    The periaqueductal or midbrain central gray matter (CG) in the rat contains a dense network of adrenergic and noradrenergic fibers. We examined the origin of this innervation by using retrograde and anterograde axonal tracers combined with immunohistochemistry for the catecholamine biosynthetic enzymes tyrosine hydroxylase (TH), dopamine beta-hydroxylase (DBH), and phenylethanolamine N-methyltransferase (PNMT). Following injections of the fluorescent tracers Fast Blue or Fluorogold into the CG, double-labeled neurons in the medulla were identified mainly in the noradrenergic A1 group in the caudal ventrolateral medulla (VLM) and A2 group in the medial part of the nucleus of the solitary tract (NTS); and in the adrenergic C1 group in the rostral ventrolateral medulla and C3 group in the rostral dorsomedial medulla. Injections of Phaseolus vulgaris-leucoagglutinin (PHA-L) into these cell groups resulted in a distinct pattern of axonal labeling in various subdivisions of the CG. Anterogradely labeled fibers originating in the medial NTS were predominantly found in the lateral portion of the dorsal raphe nucleus and in the adjacent part of the lateroventral CG (CGlv). Following PHA-L injections into the C3 region the anterogradely labeled fibers were diffusely distributed in the CGlv and the dorsal raphe nucleus at caudal levels, but rostrally tended to be located laterally in the CGlv. In contrast, ascending fibers from the caudal and rostral VLM terminated in the rostral dorsal part of the CGlv and in the dorsal nucleus of the CG, whereas ventral parts of the CG, including the dorsal raphe nucleus, contained few afferent fibers. Double-label studies with antisera against DBH and PNMT confirmed that noradrenergic neurons in the A1 and A2 groups and adrenergic neurons in the C1 and C3 groups contributed to these innervation patterns in the CGlv. Noradrenergic and adrenergic projections from the medulla to the CG may play an important role in a variety of autonomic

  5. [A man with sexual disinhibition caused by paraneoplastic limbic encephalitis].

    PubMed

    de Vries, C L; Koers, H

    2013-01-01

    A 63-year-old man with symptoms of depression and sexual disinhibition was admitted to a psychiatric clinic for the elderly. Because the man’s symptoms rapidly became more severe he was referred to the emergency room. There, his illness was diagnosed as paraneoplastic limbic encephalitis with positive anti-Hu antibodies; this is a paraneoplastic neurological syndrome presenting with short-term memory loss, epileptic seizures and psychiatric symptoms. For the prognosis of the illness it is essential that the syndrome is diagnosed as early as possible. Since patients sometimes present with mainly psychiatric symptoms it is important that psychiatrists are fully informed about the symptoms and are able to make an accurate diagnosis. PMID:23408365

  6. Cognitive Impairments Preceding and Outlasting Autoimmune Limbic Encephalitis

    PubMed Central

    Gross, Robert; Davis, Jennifer; Roth, Julie; Querfurth, Henry

    2016-01-01

    Mild cognitive impairment (MCI) can be the initial manifestation of autoimmune limbic encephalitis (ALE), a disorder that at times presents a diagnostic challenge. In addition to memory impairment, clinical features that might suggest this disorder include personality changes, agitation, insomnia, alterations of consciousness, and seizures. Once recognized, ALE typically responds to treatment with immune therapies, but long-term cognitive deficits may remain. We report two cases of patients with MCI who were ultimately diagnosed with ALE with antibodies against the voltage gated potassium channel complex. Months after apparent resolution of their encephalitides, both underwent neuropsychological testing, which demonstrated persistent cognitive deficits, primarily in the domains of memory and executive function, for cases 1 and 2, respectively. A brief review of the literature is included. PMID:26881156

  7. Neuropharmacology of 3-isobutylmethylxanthine: effects on central noradrenergic systems in vivo.

    PubMed

    Galloway, M P; Roth, R H

    1983-10-01

    We have previously shown that administration of 3-isobutyl-1-methylxanthine (IBMX) to rats causes an increase in levels of the norepinephrine (NE) metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) by a clonidine-reversible mechanism (J. Neurochem. 40: 246-251, 1983). Further investigations have revealed that IBMX administration (100 mumol/kg i.p.) stimulates noradrenergic tyrosine hydroxylation in vivo (measured after decarboxylase inhibition), an effect also reversed by the alpha-2 agonist clonidine. Consistent with previous electrophysiological data, IBMX also accelerates the disappearance of NE after inhibition of tyrosine-3-monooxygenase. When axons of the NE-dorsal bundle are mechanically severed, the effect of IBMX on MHPG is not attenuated, in contrast to the effects of the alpha-2 antagonist yohimbine which are blocked by axotomy. Administration of the adenosine agonist, 2-chloroadenosine (8 or 17 mumol/kg i.p.) or diazepam (35 mumol/kg) did not prevent the increase in MHPG caused by IBMX. The data, discussed in terms of enhanced noradrenergic activity, adenosine antagonism and phosphodiesterase inhibition, show that administration of methylxanthines (compounds known to produce anxiety and opiate withdrawal-like behaviors) results in increased biochemical activity of noradrenergic neurons in the rat. PMID:6194283

  8. The excitement of multiple noradrenergic cell groups in the rat brain related to hyperbaric oxygen seizure.

    PubMed

    Arai, Minako; Takata, Ken; Takeda, Yoshimasa; Mizobuchi, Satoshi; Morita, Kiyoshi

    2011-06-01

    The mechanism of oxygen toxicity for central nervous system and hyperbaric oxygen (HBO) seizure has not been clarified. Noradrenergic cells in the brain may contribute to HBO seizure. In this study, we defined the activation of noradrenergic cells during HBO exposure by c-fos immunohistochemistry. Electroencephalogram electrodes were pre-implanted in all animals under general anesthesia. In HBO seizure animals, HBO was induced with 5 atm of 100% oxygen until manifestation of general tonic convulsion. HBO non-seizure animals were exposed to 25 min of HBO. Control animals were put in the chamber for 120 min without pressurization. All animals were processed for c-fos immunohistochemical staining. All animals in the HBO seizure group showed electrical discharge on EEG. In the immunohistochemistry, c-fos was increased in the A1, A2 and A6 cells of the HBO seizure group, and in the A2 and A6 cells of the HBO non-seizure group, yet was extremely low in all three cell types in the control group. These results suggest the participation of noradrenaline in HBO seizure, which can be explained by the early excitement of A1 cells due to their higher sensitivity to high blood pressure, hyperoxia, or by the post-seizure activation of all noradrenergic cells. PMID:21709713

  9. Dynamic variation in forebrain estradiol levels during song learning

    PubMed Central

    Chao, Andrew; Paon, Ashley; Remage-Healey, Luke

    2014-01-01

    Estrogens shape brain circuits during development, and the capacity to synthesize estrogens locally has consequences for both sexual differentiation and the acute modulation of circuits during early learning. A recently-optimized method to detect and quantify fluctuations in brain estrogens in vivo provides a direct means to explore how brain estrogen production contributes to both differentiation and neuromodulation during development. Here, we use this method to test the hypothesis that neuroestrogens are sexually-differentiated as well as dynamically responsive to song tutoring (via passive video/audio playback) during the period of song learning in juvenile zebra finches. Our results show that baseline neuroestradiol levels in the caudal forebrain do not differ between males and females during an early critical masculinization window. Instead, we observe a prominent difference between males and females in baseline neuroestradiol that emerges during the subadult stage as animals approach sexual maturity. Second, we observe that fluctuating neuroestradiol levels during periods of passive song tutoring exhibit a markedly different profile in juveniles as compared to adults. Specifically, neuroestrogens in the caudal forebrain are elevated following (rather than during) tutor song exposure in both juvenile males and females, suggesting an important role for the early consolidation of tutor song memories. These results further reveal a circadian influence on the fluctuations in local neuroestrogens during sensory/cognitive tasks. Taken together, these findings uncover several unexpected features of brain estrogen synthesis in juvenile animals that may have implications for secondary masculinization as well as the consolidation of recent sensory experiences. PMID:25205304

  10. Learning and the motivation to eat: Forebrain circuitry

    PubMed Central

    Petrovich, Gorica D.

    2011-01-01

    Appetite and eating are not only controlled by energy needs, but also by extrinsic factors that are not directly related to energy balance. Environmental signals that acquire motivational properties through associative learning—learned cues—can override homeostatic signals and stimulate eating in sated states, or inhibit eating in states of hunger. Such influences are important, as environmental factors are believed to contribute to the increased susceptibility to overeating and the rise in obesity in the developed world. Similarly, environmental and social factors contribute to the onset and maintenance of anorexia nervosa and other eating disorders through interactions with the individual genetic background. Nevertheless, how learning enables environmental signals to control feeding, and the underlying brain mechanisms are poorly understood. We developed two rodent models to study how learned cues are integrated with homeostatic signals within functional forebrain networks, and how these networks are modulated by experience. In one model, a cue previously paired with food when an animal was hungry induces eating in sated rats. In the other model, food-deprived rats inhibit feeding when presented with a cue that signals danger, a tone previously paired with footshocks. Here evidence will be reviewed that the forebrain network formed by the amygdala, lateral hypothalamus and medial prefrontal cortex mediates cue-driven feeding, while a parallel amygdalar circuitry mediates suppression of eating by the fear cue. Findings from the animal models may be relevant for understanding aspects of human appetite and eating, and maladaptive mechanisms that could lead to overeating and anorexia. PMID:21549730

  11. Dynamic variation in forebrain estradiol levels during song learning.

    PubMed

    Chao, Andrew; Paon, Ashley; Remage-Healey, Luke

    2015-03-01

    Estrogens shape brain circuits during development, and the capacity to synthesize estrogens locally has consequences for both sexual differentiation and the acute modulation of circuits during early learning. A recently optimized method to detect and quantify fluctuations in brain estrogens in vivo provides a direct means to explore how brain estrogen production contributes to both differentiation and neuromodulation during development. Here, we use this method to test the hypothesis that neuroestrogens are sexually differentiated as well as dynamically responsive to song tutoring (via passive video/audio playback) during the period of song learning in juvenile zebra finches. Our results show that baseline neuroestradiol levels in the caudal forebrain do not differ between males and females during an early critical masculinization window. Instead, we observe a prominent difference between males and females in baseline neuroestradiol that emerges during the subadult stage as animals approach sexual maturity. Second, we observe that fluctuating neuroestradiol levels during periods of passive song tutoring exhibit a markedly different profile in juveniles as compared to adults. Specifically, neuroestrogens in the caudal forebrain are elevated following (rather than during) tutor song exposure in both juvenile males and females, suggesting an important role for the early consolidation of tutor song memories. These results further reveal a circadian influence on the fluctuations in local neuroestrogens during sensory/cognitive tasks. Taken together, these findings uncover several unexpected features of brain estrogen synthesis in juvenile animals that may have implications for secondary masculinization as well as the consolidation of recent sensory experiences. PMID:25205304

  12. Limbic Encephalitis Associated With GAD65 Antibodies: Brief Review of the Relevant literature.

    PubMed

    Gagnon, Maude-Marie; Savard, Martin

    2016-07-01

    Recently, many cases of autoimmune limbic encephalitis with positive GAD65 (glutamic acid decarboxylase) antibodies have been described in the scientific literature. However, it remains an understudied topic of great relevance to practicing neurologists. Thus, we report here a review of published cases, in English, of autoimmune limbic encephalitis with this type of antibodies, focusing on presenting symptoms and signs, associated conditions, and findings upon investigation. We also report treatment responses. We aim to offer a better description of the clinical spectrum of autoimmune limbic encephalitis associated with GAD65 antibodies as well as to expose its paraclinical features and outcome. PMID:27030381

  13. Thalamic changes in mesial temporal sclerosis: a limbic system pathology. A case report.

    PubMed

    Caranci, F; Bartiromo, F; Cirillo, L; Aiello, A; Cirillo, S; Brunetti, A

    2007-04-30

    Hippocampal abnormalities correlated with mesial temporal sclerosis (MTS) are well documented. MTS may be associated with extrahippocampal anomalies involving limbic structures along a known neuroanatomic pathway (Papez circuit). We report a patient with MTS and thalamic changes. Seizure-related thalamic damage could have been caused by abnormal electric discharges from the mamillary body to the anterior thalamus through the mamillothalamic tract. This suggests that MTS is not limited to the temporal lobe but could represent a limbic system pathology. PMID:24299648

  14. Habituation of human limbic neuronal response to sensory stimulation.

    PubMed

    Wilson, C L; Babb, T L; Halgren, E; Wang, M L; Crandall, P H

    1984-04-01

    Hippocampal, parahippocampal gyrus, and amygdalar neuronal responses to visual and acoustic stimuli were analyzed during trains of several hundred stimulus repetitions as part of an investigation of sensory pathways to medial temporal lobe structures in complex-partial epilepsy patients who were being monitored with depth electrodes. Ten percent of more than 500 single and multiple units tested were responsive to simple sensory stimuli. The majority of the responsive units were recorded in the posterior parahippocampal gyrus (HG) during visual stimulation. Although neurons in pes hippocampi (PH; Ammons's horn) were also responsive to photic stimuli, no visually responsive units were found in amygdala. Very few units were responsive to acoustic stimuli, and these were found only in PH and amygdala, and not in HG. Significant trends of increase or decrease in response amplitude during trains of stimuli were found in all acoustically responsive units. Significant trends of visual response amplitude increase or decrease were found in 20% of PH units, and in 44% of HG units. Mean latencies of acoustically responsive units were longer than those of visually responsive units, and latencies of PH sensory units showing decremental response were longer than nondecremental PH units. Rate of response decrement was usually linear for acoustic responses and exponential for visual responses. The response dynamics of medial temporal lobe neurons are compared with those described in the animal limbic system and are related to habituation of human sensory evoked scalp potentials. PMID:6705888

  15. Basal Forebrain Atrophy Contributes to Allocentric Navigation Impairment in Alzheimer’s Disease Patients

    PubMed Central

    Kerbler, Georg M.; Nedelska, Zuzana; Fripp, Jurgen; Laczó, Jan; Vyhnalek, Martin; Lisý, Jiří; Hamlin, Adam S.; Rose, Stephen; Hort, Jakub; Coulson, Elizabeth J.

    2015-01-01

    The basal forebrain degenerates in Alzheimer’s disease (AD) and this process is believed to contribute to the cognitive decline observed in AD patients. Impairment in spatial navigation is an early feature of the disease but whether basal forebrain dysfunction in AD is responsible for the impaired navigation skills of AD patients is not known. Our objective was to investigate the relationship between basal forebrain volume and performance in real space as well as computer-based navigation paradigms in an elderly cohort comprising cognitively normal controls, subjects with amnestic mild cognitive impairment and those with AD. We also tested whether basal forebrain volume could predict the participants’ ability to perform allocentric- vs. egocentric-based navigation tasks. The basal forebrain volume was calculated from 1.5 T magnetic resonance imaging (MRI) scans, and navigation skills were assessed using the human analog of the Morris water maze employing allocentric, egocentric, and mixed allo/egocentric real space as well as computerized tests. When considering the entire sample, we found that basal forebrain volume correlated with spatial accuracy in allocentric (cued) and mixed allo/egocentric navigation tasks but not the egocentric (uncued) task, demonstrating an important role of the basal forebrain in mediating cue-based spatial navigation capacity. Regression analysis revealed that, although hippocampal volume reflected navigation performance across the entire sample, basal forebrain volume contributed to mixed allo/egocentric navigation performance in the AD group, whereas hippocampal volume did not. This suggests that atrophy of the basal forebrain contributes to aspects of navigation impairment in AD that are independent of hippocampal atrophy. PMID:26441643

  16. Basal Forebrain Atrophy Contributes to Allocentric Navigation Impairment in Alzheimer's Disease Patients.

    PubMed

    Kerbler, Georg M; Nedelska, Zuzana; Fripp, Jurgen; Laczó, Jan; Vyhnalek, Martin; Lisý, Jiří; Hamlin, Adam S; Rose, Stephen; Hort, Jakub; Coulson, Elizabeth J

    2015-01-01

    The basal forebrain degenerates in Alzheimer's disease (AD) and this process is believed to contribute to the cognitive decline observed in AD patients. Impairment in spatial navigation is an early feature of the disease but whether basal forebrain dysfunction in AD is responsible for the impaired navigation skills of AD patients is not known. Our objective was to investigate the relationship between basal forebrain volume and performance in real space as well as computer-based navigation paradigms in an elderly cohort comprising cognitively normal controls, subjects with amnestic mild cognitive impairment and those with AD. We also tested whether basal forebrain volume could predict the participants' ability to perform allocentric- vs. egocentric-based navigation tasks. The basal forebrain volume was calculated from 1.5 T magnetic resonance imaging (MRI) scans, and navigation skills were assessed using the human analog of the Morris water maze employing allocentric, egocentric, and mixed allo/egocentric real space as well as computerized tests. When considering the entire sample, we found that basal forebrain volume correlated with spatial accuracy in allocentric (cued) and mixed allo/egocentric navigation tasks but not the egocentric (uncued) task, demonstrating an important role of the basal forebrain in mediating cue-based spatial navigation capacity. Regression analysis revealed that, although hippocampal volume reflected navigation performance across the entire sample, basal forebrain volume contributed to mixed allo/egocentric navigation performance in the AD group, whereas hippocampal volume did not. This suggests that atrophy of the basal forebrain contributes to aspects of navigation impairment in AD that are independent of hippocampal atrophy. PMID:26441643

  17. Basal forebrain neuronal inhibition enables rapid behavioral stopping

    PubMed Central

    Mayse, Jeffrey D.; Nelson, Geoffrey M.; Avila, Irene; Gallagher, Michela; Lin, Shih-Chieh

    2015-01-01

    Cognitive inhibitory control, the ability to rapidly suppress responses inappropriate for the context, is essential for flexible and adaptive behavior. While most studies on inhibitory control have focused on the fronto-basal-ganglia circuit, here we explore a novel hypothesis and show that rapid behavioral stopping is enabled by neuronal inhibition in the basal forebrain (BF). In rats performing the stop signal task, putative noncholinergic BF neurons with phasic bursting responses to the go signal were inhibited nearly completely by the stop signal. The onset of BF neuronal inhibition was tightly coupled with and temporally preceded the latency to stop, the stop signal reaction time. Artificial inhibition of BF activity in the absence of the stop signal was sufficient to reproduce rapid behavioral stopping. These results reveal a novel subcortical mechanism of rapid inhibitory control by the BF, which provides bidirectional control over the speed of response generation and inhibition. PMID:26368943

  18. Visualization of growth factor receptor sites in rat forebrain

    SciTech Connect

    Quirion, R.; Araujo, D.; Nair, N.P.; Chabot, J.G.

    1988-01-01

    It is now known that various growth factors may also act in the central nervous system. Among them, it has recently been shown that epidermal growth factor (EGF) and insulin-like growth factor I (IGF-I) may possess trophic effects in the mammalian brain. We report here on the respective autoradiographic distribution of (/sup 125/I)EGF and (/sup 125/I)IGF-I receptor binding sites in the rat brain, both during ontogeny and in adulthood. It appears that (/sup 125/I)EGF sites are mostly found in the rat forebrain during brain development. On the other hand, (/sup 125/I)IGF-I sites are more widely distributed both during ontogeny and in adulthood. These results reveal the plasticity of the expression of EGF and IGF-I receptor sites in the mammalian brain. This could be relevant for the respective role of these two growth factors in the development and maintenance of neuronal function.

  19. Beyond the olfactory bulb: An odotopic map in the forebrain

    PubMed Central

    Nikonov, Alexander A.; Finger, Thomas E.; Caprio, John

    2005-01-01

    We report electrophysiological evidence that a simple odotopy, the spatial mapping of different odorants, is maintained above the level of the olfactory bulb (OB). Three classes of biologically relevant odorants for fish are processed in distinct regions of the forebrain (FB) in the channel catfish. Feeding cues, mainly amino acids and nucleotides, are represented in lateral, pallial portions of the FB, equivalent to the olfactory cortex of amniote vertebrates, whereas social signals mediated by bile salts are represented in medial FB centers, possibly homologous to portions of the amygdala. As in the OB, the different odorant classes map onto different territories; however, the response properties of units of the olfactory areas of the FB do not simply mirror those of the OB. For some units, distinctive response properties emerged, because the FB is the first center where odors subserving a common behavioral function (i.e., food function) converge. PMID:16339016

  20. The dopaminergic projection system, basal forebrain macrosystems, and conditioned stimuli

    PubMed Central

    Zahm, Daniel S.

    2011-01-01

    This review begins with a description of some problems that in recent years have beset an influential circuit model of fear-conditioning and goes on to look at neuroanatomy that might subserve conditioning viewed in a broader perspective, including not only fear, but also appetitive, conditioning. The paper then focuses on basal forebrain functional-anatomical systems, or macrosystems, as they have come to be called, which Lennart Heimer and colleagues described beginning in the 1970’s. Yet more specific attention is then given to the relationships of the dorsal and ventral striatopallidal systems and extended amygdala with the dopaminergic mesotelencephalic projection systems, culminating with the hypothesis that all macrosystems contribute to behavioral conditioning. PMID:18204412

  1. Auditory-limbic interactions in chronic tinnitus: Challenges for neuroimaging research.

    PubMed

    Leaver, Amber M; Seydell-Greenwald, Anna; Rauschecker, Josef P

    2016-04-01

    Tinnitus is a widespread auditory disorder affecting approximately 10-15% of the population, often with debilitating consequences. Although tinnitus commonly begins with damage to the auditory system due to loud-noise exposure, aging, or other etiologies, the exact neurophysiological basis of chronic tinnitus remains unknown. Many researchers point to a central auditory origin of tinnitus; however, a growing body of evidence also implicates other brain regions, including the limbic system. Correspondingly, we and others have proposed models of tinnitus in which the limbic and auditory systems both play critical roles and interact with one another. Specifically, we argue that damage to the auditory system generates an initial tinnitus signal, consistent with previous research. In our model, this "transient" tinnitus is suppressed when a limbic frontostriatal network, comprised of ventromedial prefrontal cortex and ventral striatum, successfully modulates thalamocortical transmission in the auditory system. Thus, in chronic tinnitus, limbic-system damage and resulting inefficiency of auditory-limbic interactions prevents proper compensation of the tinnitus signal. Neuroimaging studies utilizing connectivity methods like resting-state fMRI and diffusion MRI continue to uncover tinnitus-related anomalies throughout auditory, limbic, and other brain systems. However, directly assessing interactions between these brain regions and networks has proved to be more challenging. Here, we review existing empirical support for models of tinnitus stressing a critical role for involvement of "non-auditory" structures in tinnitus pathophysiology, and discuss the possible impact of newly refined connectivity techniques from neuroimaging on tinnitus research. PMID:26299843

  2. Blood-brain barrier changes with kainic acid-induced limbic seizures

    SciTech Connect

    Zucker, D.K.; Wooten, G.F.; Lothman, E.W.

    1983-02-01

    Rats were treated with kainic acid (KA) i.v. to produce increasingly severe limbic seizures that were monitored with a behavioral rating scale. At various times after the induction of seizures, the animals; blood-brain barriers (B-BB) were studied with alpha-(/sup 14/C)aminoisobutyric acid ((/sup 14/C)AIBA) autoradiography. Using optical density ratios, a coefficient was devised to assess the functional integrity of the B-BB in discrete anatomic regions and to quantitatively compare these measurements among different groups of experimental animals. In animals that exhibited only mild seizures, the B-BB was not different from controls. Animals with severe limbic seizures, however, showed alterations. For as long as 2 h after delivery of KA, the B-BB appeared normal; from 2 to 24 h, the permeability to (/sup 14/C)AIBA was markedly increased throughout the brain, especially in limbic regions; from 24 h to 7 days the B-BB returned to normal except for a small residual change in limbic structures. These findings were confirmed with Evans blue dye studies of the B-BB. A correlation between focal accentuation of B-BB alterations and neuropathologic changes was found. These experiments indicted that recurrent limbic seizures may lead to a breakdown in the B-BB independent of systemic metabolic derangements. Marked focal metabolic and electrical changes, however, occurred in several limbic structures several hours before the blood-brain barrier was altered.

  3. Prenatal drug exposures sensitize noradrenergic circuits to subsequent disruption by chlorpyrifos.

    PubMed

    Slotkin, Theodore A; Skavicus, Samantha; Seidler, Frederic J

    2015-12-01

    We examined whether nicotine or dexamethasone, common prenatal drug exposures, sensitize the developing brain to chlorpyrifos. We gave nicotine to pregnant rats throughout gestation at a dose (3mg/kg/day) producing plasma levels typical of smokers; offspring were then given chlorpyrifos on postnatal days 1-4, at a dose (1mg/kg) that produces minimally-detectable inhibition of brain cholinesterase activity. In a parallel study, we administered dexamethasone to pregnant rats on gestational days 17-19 at a standard therapeutic dose (0.2mg/kg) used in the management of preterm labor, followed by postnatal chlorpyrifos. We evaluated cerebellar noradrenergic projections, a known target for each agent, and contrasted the effects with those in the cerebral cortex. Either drug augmented the effect of chlorpyrifos, evidenced by deficits in cerebellar β-adrenergic receptors; the receptor effects were not due to increased systemic toxicity or cholinesterase inhibition, nor to altered chlorpyrifos pharmacokinetics. Further, the deficits were not secondary adaptations to presynaptic hyperinnervation/hyperactivity, as there were significant deficits in presynaptic norepinephrine levels that would serve to augment the functional consequence of receptor deficits. The pretreatments also altered development of cerebrocortical noradrenergic circuits, but with a different overall pattern, reflecting the dissimilar developmental stages of the regions at the time of exposure. However, in each case the net effects represented a change in the developmental trajectory of noradrenergic circuits, rather than simply a continuation of an initial injury. Our results point to the ability of prenatal drug exposure to create a subpopulation with heightened vulnerability to environmental neurotoxicants. PMID:26419632

  4. Retrograde adenoviral vector targeting of nociresponsive pontospinal noradrenergic neurons in the rat in vivo

    PubMed Central

    Howorth, Patrick W; Teschemacher, Anja G; Pickering, Anthony E

    2009-01-01

    The spinal dorsal horn receives a dense innervation of noradrenaline-containing fibers that originate from pontine neurons in the A5, locus coeruleus (LC), and A7 cell groups. These pontospinal neurons are believed to constitute a component of the endogenous analgesic system. We used an adenoviral vector with a catecholaminergic-selective promoter (AVV-PRS) to retrogradely label the noradrenergic neurons projecting to the lumbar (L4–L5) dorsal horn with enhanced green fluorescent protein (EGFP) or monomeric red fluorescent protein (mRFP). Retrogradely labeled neurons (145 ± 12, n = 14) were found in A5-12%, LC-80% and A7-8% after injection of AVV-PRS-EGFP to the dorsal horn of L4–L5. These neurons were immunopositive for dopamine β-hydroxylase, indicating that they were catecholaminergic. Retrograde labeling was optimal 7 days after injection, persisted for over 4 weeks, and was dependent on viral vector titer. The spinal topography of the noradrenergic projection was examined using EGFP- and mRFP-expressing adenoviral vectors. Pontospinal neurons provide bilateral innervation of the cord and there was little overlap in the distribution of neurons projecting to the cervical and lumbar regions. The axonal arbor of the pontospinal neurons was visualized with GFP immunocytochemistry to show projections to the inferior olive, cerebellum, thalamus, and cortex but not to the hippocampus or caudate putamen. Formalin testing evoked c-fos expression in these pontospinal neurons, suggesting that they were nociresponsive (A5-21%, LC-16%, and A7-26%, n = 8). Thus, we have developed a viral vector-based strategy to selectively, retrogradely target the pontospinal noradrenergic neurons that are likely to be involved in the descending control of nociception. PMID:19003793

  5. Genetically determined differences in noradrenergic function: The spontaneously hypertensive rat model.

    PubMed

    Sterley, Toni-Lee; Howells, Fleur M; Russell, Vivienne A

    2016-06-15

    While genetic predisposition is a major factor, it is not known how development of attention-deficit/hyperactivity disorder (ADHD) is modulated by early life stress. The spontaneously hypertensive rat (SHR) displays the behavioral characteristics of ADHD (poorly sustained attention, impulsivity, hyperactivity) and is the most widely studied genetic model of ADHD. We have previously shown that SHR have disturbances in the noradrenergic system and that the early life stress of maternal separation failed to produce anxiety-like behavior in SHR, contrary to control Sprague-Dawley and Wistar-Kyoto (WKY) who showed typical anxiety-like behavior in later life. In the present study we investigated the effect of maternal separation on approach behavior (response to a novel object in a familiar environment) in preadolescent SHR and WKY. We also investigated whether maternal separation altered GABAA and NMDA receptor-mediated regulation of norepinephrine release in preadolescent SHR and WKY hippocampus. We found that female SHR, similar to male SHR, exhibited greater exploratory activity than WKY. Maternal separation significantly increased GABAA receptor-mediated inhibition of glutamate-stimulated release of norepinephrine in male and female SHR hippocampus but had no significant effect in WKY. Maternal separation had opposite effects on NMDA receptor-mediated inhibition of norepinephrine release in SHR and WKY hippocampus, as it increased inhibition of both glutamate-stimulated and depolarization-evoked release in SHR hippocampus but not in WKY. The results of the present study show that noradrenergic function is similarly altered by the early life stress of maternal separation in male and female SHR, while GABA- and glutamate-regulation of norepinephrine release remained unaffected by maternal separation in the control, WKY, rat strain. This article is part of a Special Issue entitled SI: Noradrenergic System. PMID:26612520

  6. Effect of rovatirelin, a novel thyrotropin-releasing hormone analog, on the central noradrenergic system.

    PubMed

    Ijiro, Tomoyuki; Nakamura, Kayo; Ogata, Masanori; Inada, Hiroyuki; Kiguchi, Sumiyoshi; Maruyama, Kazuyasu; Nabekura, Junichi; Kobayashi, Mamoru; Ishibashi, Hitoshi

    2015-08-15

    Rovatirelin ([1-[-[(4S,5S)-(5-methyl-2-oxo oxazolidin-4-yl) carbonyl]-3-(thiazol-4-yl)-l-alanyl]-(2R)-2-methylpyrrolidine) is a novel synthetic agent that mimics the actions of thyrotropin-releasing hormone (TRH). The aim of this study was to investigate the electrophysiological and pharmacological effects of rovatirelin on the central noradrenergic system and to compare the results with those of another TRH mimetic agent, taltirelin, which is approved for the treatment of spinocerebellar degeneration (SCD) in Japan. Rovatirelin binds to the human TRH receptor with higher affinity (Ki=702nM) than taltirelin (Ki=3877nM). Rovatirelin increased the spontaneous firing of action potentials in the acutely isolated noradrenergic neurons of rat locus coeruleus (LC). The facilitatory action of rovatirelin on the firing rate in the LC neurons was inhibited by the TRH receptor antagonist, chlordiazepoxide. Reduction of the extracellular pH increased the spontaneous firing of LC neurons and rovatirelin failed to increase the firing frequency further, indicating an involvement of acid-sensitive K+ channels in the rovatirelin action. In in vivo studies, oral administration of rovatirelin increased both c-Fos expression in the LC and extracellular levels of noradrenaline (NA) in the medial prefrontal cortex (mPFC) of rats. Furthermore, rovatirelin increased locomotor activity. The increase in NA level and locomotor activity by rovatirelin was more potent and longer acting than those by taltirelin. These results indicate that rovatirelin exerts a central nervous system (CNS)-mediated action through the central noradrenergic system, which is more potent than taltirelin. Thus, rovatirelin may have an orally effective therapeutic potential in patients with SCD. PMID:26142830

  7. The Sensory Impact of Nicotine on Noradrenergic and Dopaminergic Neurons of the Nicotine Reward - Addiction Neurocircuitry

    PubMed Central

    Rose, Jed E; Dehkordi, Ozra; Manaye, Kebreten F; Millis, Richard M; Cianaki, Salman Ameri; Jayam-Trouth, Annapurni

    2016-01-01

    The sensory experience of smoking is a key component of nicotine addiction known to result, in part, from stimulation of nicotinic acetylcholine receptors (nAChRs) at peripheral sensory nerve endings. Such stimulation of nAChRs is followed by activation of neurons at multiple sites in the mesocorticolimbic reward pathways. However, the neurochemical profiles of CNS cells that mediate the peripheral sensory impact of nicotine remain unknown. In the present study in mice, we first used c-Fos immunohistochemistry to identify CNS cells stimulated by nicotine (NIC, 40 μg/kg, IP) and by a peripherally-acting analog of nicotine, nicotine pyrrolidine methiodide (NIC-PM, 30 μg/kg, IP). Sequential double-labelling was then performed to determine whether noradrenergic and dopaminergic neurons of the nicotine reward-addiction circuitry were primary targets of NIC and NIC-PM. Double-labelling of NIC and/or NIC-PM activated c-Fos immunoreactive cells with tyrosine hydroxylase (TH) showed no apparent c-Fos expression by the dopaminergic cells of the ventral tegmental area (VTA). With the exception of sparse numbers of TH immunoreactive D11 cells, dopamine-containing neurons in other areas of the reward-addiction circuitry, namely periaqueductal gray, and dorsal raphe, were also devoid of c-Fos immunoreactivity. Noradrenergic neurons of locus coeruleus (LC), known to innervate VTA, were activated by both NIC and NIC-PM. These results demonstrate that noradrenergic neurons of LC are among the first structures that are stimulated by single acute IP injection of NIC and NIC-PM. Dopaminergic neurons of VTA and other CNS sites, did not respond to acute IP administration of NIC or NIC-PM by induction of c-Fos. PMID:27347434

  8. Autoradiographic analysis of alpha 1-noradrenergic receptors in the human brain postmortem. Effect of suicide

    SciTech Connect

    Gross-Isseroff, R.; Dillon, K.A.; Fieldust, S.J.; Biegon, A. )

    1990-11-01

    In vitro quantitative autoradiography of alpha 1-noradrenergic receptors, using tritiated prazosin as a ligand, was performed on 24 human brains postmortem. Twelve brains were obtained from suicide victims and 12 from matched controls. We found significant lower binding to alpha 1 receptors in several brain regions of the suicide group as compared with matched controls. This decrease in receptor density was evident in portions of the prefrontal cortex, as well as the temporal cortex and in the caudate nucleus. Age, sex, presence of alcohol, and time of death to autopsy did not affect prazosin binding, in our sample, as measured by autoradiography.

  9. AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location

    PubMed Central

    Lai, Meizan; Hughes, Ethan G.; Peng, Xiaoyu; Zhou, Lei; Gleichman, Amy J.; Shu, Huidy; Matà, Sabrina; Kremens, Daniel; Vitaliani, Roberta; Geschwind, Michael D.; Bataller, Luis; Kalb, Robert G.; Davis, Rebecca; Graus, Francesc; Lynch, David R.; Balice-Gordon, Rita; Dalmau, Josep

    2009-01-01

    Background Limbic encephalitis (LE) frequently associates with antibodies to cell surface antigens. Characterization of these antigens is important because it facilitates the diagnosis of those disorders that are treatment-responsive. We report a novel antigen of LE and the effect of patients' antibodies on neuronal cultures. Methods Clinical analysis of 10 patients with LE. Immunoprecipitation and mass spectrometry were used to identify the antigens. HEK293 cells expressing the antigens were used in immunocytochemistry and ELISA. The effect of patients' antibodies on cultures of live rat hippocampal neurons was determined with confocal microscopy. Results Median age was 60 years (38-87); 9 were women. Seven had tumors of the lung, breast or thymus. Nine patients responded to immunotherapy or oncological therapy but neurologic relapses, without tumor recurrence, were frequent and influenced the long-term outcome. One untreated patient died of LE. All patients had antibodies against neuronal cell surface antigens that by immunoprecipitation were found to be the GluR1 and GluR2 subunits of the AMPA receptor (AMPAR). HEK293 cells expressing GluR1/2 reacted with all patients' sera or CSF, providing a diagnostic test for the disorder. Application of antibodies to cultures of neurons significantly decreased the number of GluR2-containing AMPAR clusters at synapses with a smaller decrease in overall AMPAR cluster density; these effects were reversed after antibody removal. Conclusions Antibodies to GluR1/2 associate with LE that is often paraneoplastic, treatment-responsive, and has a tendency to relapse. Our findings support an antibody-mediated pathogenesis in which patients' antibodies alter the synaptic localization and number of AMPAR. PMID:19338055

  10. Neurodevelopment Genes in Lampreys Reveal Trends for Forebrain Evolution in Craniates

    PubMed Central

    Guérin, Adèle; d'Aubenton-Carafa, Yves; Marrakchi, Emna; Da Silva, Corinne; Wincker, Patrick; Mazan, Sylvie; Rétaux, Sylvie

    2009-01-01

    The forebrain is the brain region which has undergone the most dramatic changes through vertebrate evolution. Analyses conducted in lampreys are essential to gain insight into the broad ancestral characteristics of the forebrain at the dawn of vertebrates, and to understand the molecular basis for the diversifications that have taken place in cyclostomes and gnathostomes following their splitting. Here, we report the embryonic expression patterns of 43 lamprey genes, coding for transcription factors or signaling molecules known to be involved in cell proliferation, stemcellness, neurogenesis, patterning and regionalization in the developing forebrain. Systematic expression patterns comparisons with model organisms highlight conservations likely to reflect shared features present in the vertebrate ancestors. They also point to changes in signaling systems –pathways which control the growth and patterning of the neuroepithelium-, which may have been crucial in the evolution of forebrain anatomy at the origin of vertebrates. PMID:19399187

  11. Noradrenergic refinement of glutamatergic neuronal circuits in the lateral superior olivary nucleus before hearing onset

    PubMed Central

    Hirao, Kenzo; Eto, Kei; Nakahata, Yoshihisa; Ishibashi, Hitoshi; Nagai, Taku

    2015-01-01

    Neuronal circuit plasticity during development is fundamental for precise network formation. Pioneering studies of the developmental visual cortex indicated that noradrenaline (NA) is crucial for ocular dominance plasticity during the critical period in the visual cortex. Recent research demonstrated tonotopic map formation by NA during the critical period in the auditory system, indicating that NA also contributes to synaptic plasticity in this system. The lateral superior olive (LSO) in the auditory system receives glutamatergic input from the ventral cochlear nucleus (VCN) and undergoes circuit remodeling during postnatal development. LSO is innervated by noradrenergic afferents and is therefore a suitable model to study the function of NA in refinement of neuronal circuits. Chemical lesions of the noradrenergic system and chronic inhibition of α2-adrenoceptors in vivo during postnatal development in mice disrupted functional elimination and strengthening of VCN-LSO afferents. This was potentially mediated by activation of presynaptic α2-adrenoceptors and inhibition of glutamate release because NA presynaptically suppressed excitatory postsynaptic current (EPSC) through α2-adrenoceptors during the first two postnatal weeks in an in vitro study. Furthermore, NA and α2-adrenoceptor agonist induced long-term suppression of EPSCs and decreased glutamate release. These results suggest that NA has a critical role in synaptic refinement of the VCN-LSO glutamatergic pathway through failure of synaptic transmission. Because of the ubiquitous distribution of NA afferents and the extensive expression of α2-adrenoceptors throughout the immature brain, this phenomenon might be widespread in the developing central nervous system. PMID:26203112

  12. Noradrenergic refinement of glutamatergic neuronal circuits in the lateral superior olivary nucleus before hearing onset.

    PubMed

    Hirao, Kenzo; Eto, Kei; Nakahata, Yoshihisa; Ishibashi, Hitoshi; Nagai, Taku; Nabekura, Junichi

    2015-09-01

    Neuronal circuit plasticity during development is fundamental for precise network formation. Pioneering studies of the developmental visual cortex indicated that noradrenaline (NA) is crucial for ocular dominance plasticity during the critical period in the visual cortex. Recent research demonstrated tonotopic map formation by NA during the critical period in the auditory system, indicating that NA also contributes to synaptic plasticity in this system. The lateral superior olive (LSO) in the auditory system receives glutamatergic input from the ventral cochlear nucleus (VCN) and undergoes circuit remodeling during postnatal development. LSO is innervated by noradrenergic afferents and is therefore a suitable model to study the function of NA in refinement of neuronal circuits. Chemical lesions of the noradrenergic system and chronic inhibition of α2-adrenoceptors in vivo during postnatal development in mice disrupted functional elimination and strengthening of VCN-LSO afferents. This was potentially mediated by activation of presynaptic α2-adrenoceptors and inhibition of glutamate release because NA presynaptically suppressed excitatory postsynaptic current (EPSC) through α2-adrenoceptors during the first two postnatal weeks in an in vitro study. Furthermore, NA and α2-adrenoceptor agonist induced long-term suppression of EPSCs and decreased glutamate release. These results suggest that NA has a critical role in synaptic refinement of the VCN-LSO glutamatergic pathway through failure of synaptic transmission. Because of the ubiquitous distribution of NA afferents and the extensive expression of α2-adrenoceptors throughout the immature brain, this phenomenon might be widespread in the developing central nervous system. PMID:26203112

  13. alpha1-noradrenergic receptor antagonism blocks dependence-induced increases in responding for ethanol.

    PubMed

    Walker, Brendan M; Rasmussen, Dennis D; Raskind, Murray A; Koob, George F

    2008-03-01

    The purpose of this study was to test the hypothesis that blockade of alpha1-adrenergic receptors may suppress the excessive ethanol consumption associated with acute withdrawal in ethanol-dependent rats. Following the acquisition and stabilization of operant ethanol self-administration in male Wistar rats, dependence was induced in half the animals by subjecting them to a 4-week intermittent vapor exposure period in which animals were exposed to ethanol vapor for 14h/day. Subsequent to dependence induction, the effect of alpha1-noradrenergic receptor antagonist prazosin (0.0, 0.25, 0.5, 1, 1.5, and 2.0mg/kg IP) was tested on operant responding for ethanol in vapor-exposed and control rats during acute withdrawal. In ethanol-dependent animals, prazosin significantly suppressed responding at the 1.5 and 2.0mg/kg doses, whereas only the 2.0mg/kg dose was effective in nondependent animals, identifying an increase in the sensitivity to prazosin in dependent animals. Conversely, at the lowest dose tested (0.25mg/kg), prazosin increased responding in nondependent animals, which is consistent with the effect of anxiolytics on ethanol self-administration in nondependent animals. None of the doses tested reliably affected concurrent water self-administration. These results suggest the involvement of the noradrenergic system in the excessive alcohol drinking seen during acute withdrawal in ethanol-dependent rats. PMID:18358987

  14. Noradrenergic-Dopaminergic Interactions Due to DSP-4-MPTP Neurotoxin Treatments: Iron Connection.

    PubMed

    Archer, Trevor

    2016-01-01

    The investigations of noradrenergic lesions and dopaminergic lesions have established particular profiles of functional deficits and accompanying alterations of biomarkers in brain regions and circuits. In the present account, the focus of these lesions is directed toward the effects upon dopaminergic neurotransmission and expression that are associated with the movement disorders and psychosis-like behavior. In this context, it was established that noradrenergic denervation, through administration of the selective noradrenaline (NA) neurotoxin, DSP-4, should be performed prior to the depletion of dopamine (DA) with the selective neurotoxin, MPTP. Employing this regime, it was shown that (i) following DSP-4 (50 mg/kg) pretreatment of C57/Bl6 mice, both the functional and neurochemical (DA loss) effects of MPTP (2 × 20 and 2 × 40 mg/kg) were markedly exacerbated, and (ii) following postnatal iron (Fe(2+), 7.5 mg/kg, on postnatal days 19-12), pretreatment with DSP-4 followed by the lower 2 × 20 mg/kg MPTP dose induced even greater losses of motor behavior and striatal DA. As yet, the combination of NA-DA depletions, and even more so Fe(2+)-NA-DA depletion, has been considered to present a movement disorder aspect although studies exploring cognitive domains are lacking. With intrusion of iron overload into this formula, the likelihood of neuropsychiatric disorder, as well, unfolds. PMID:26718588

  15. Increased Task Difficulty Results in Greater Impact of Noradrenergic Modulation of Cognitive Flexibility

    PubMed Central

    Campbell, Heather L.; Tivarus, Madalina E.; Hillier, Ashleigh; Beversdorf, David Q.

    2008-01-01

    Previous research suggests that the noradrenergic system modulates certain types of cognitive flexibility. This study compared various doses of beta-adrenergic antagonists for their effect on cognitive flexibility in problem solving, and how task difficulty interacts with this effect, as well as the effect of beta-adrenergic antagonists on other tasks. Anagram task performance was compared in 72 subjects using a within-subject design for propranolol at 20mg, 40mg, 60mg, and placebo in a double-blinded manner, and the effects of subject ability and task difficulty were examined. We also examined the effect of the 40mg propranolol dose on a range of other tasks. Overall, more anagram problems were solved while on propranolol 40mg than on placebo. Subjects least able to solve the problems benefited significantly from 40mg of propranolol. Also, for all subjects the most difficult problems were solved more quickly with propranolol 40mg than placebo. Benefits were also seen for word fluency and backward digit span. Therefore, noradrenergic modulation of cognitive flexibility is affected by how much difficulty the subject is encountering when searching for the solution, a pattern consistent with what might be expected in an effect on the search of the semantic and associative network. PMID:17884154

  16. Central noradrenergic mechanisms and the acute stress response during painful stimulation.

    PubMed

    Chapman, C Richard; Bradshaw, David H; Donaldson, Gary W; Jacobson, Robert C; Nakamura, Yoshio

    2014-12-01

    Events that threaten tissue integrity including noxious stimulation activate central noradrenergic circuits, particularly locus coeruleus and its projections. Recent advances in theory hold that an adaptive, defensive shift in brain activity takes place in response to threat. In principle, this shift may accentuate the autonomic and central biomarkers of the perception of painful events and the experience of pain itself. We have examined the effects of an alpha-2 agonist on pupil dilation responses, skin conductance responses, near field somatosensory evoked potentials and pain reports in normal volunteers undergoing repeated trials of painful fingertip stimulation delivered at low, medium and high intensities. In a double-blinded study, 114 healthy male and female volunteers underwent repeated noxious stimulation under baseline, placebo and active drug conditions where the active drug was the alpha-2 agonist tizanidine 4 mg. In contrast to baseline and placebo conditions, tizanidine 4 mg significantly reduced the magnitudes of the mean pupil dilation response, the mean skin conductance response, the mean near field somatosensory evoked potential peak-to-peak amplitude and the mean pain intensity rating. Stimulus intensity significantly altered all three biomarkers and the pain report in a graded fashion. There were no sex differences. These findings support the hypotheses that painful events activate central noradrenergic circuits, and that these circuits play a role in the autonomic and central arousal associated with pain. PMID:25122041

  17. A shift of paradigm: from noradrenergic to dopaminergic modulation of learning?

    PubMed

    Breitenstein, Caterina; Flöel, Agnes; Korsukewitz, Catharina; Wailke, Stefanie; Bushuven, Stefan; Knecht, Stefan

    2006-10-25

    d-Amphetamine coupled with behavioral training has been effective for improving functional recovery after stroke. d-amphetamine acts on multiple brain transmitter systems, but the recovery enhancing effect has been attributed to its noradrenergic actions. Another potent modulator of learning is dopamine, which may also enhance stroke recovery in humans. Based on data from previous studies of our group, we compared the learning enhancing effects of d-amphetamine with a more selective dopaminergic substance (levodopa) in identical protocols. Using a prospective, randomized, double-blind, placebo-controlled design, we had taught 60 male healthy subjects a miniature lexicon of 50 concrete nouns over the course of five consecutive training days using an associative learning principle. Subjects had received either d-amphetamine (0.25 mg/kg), levodopa/carbidopa (fixed dose of 100/25 mg), or placebo 90 min prior to training on each of the 5 days. Novel word learning was significantly enhanced in both the d-amphetamine and levodopa groups as compared to the placebo group. The learning superiority was maintained at the two re-assessments (1 week and 1 month post training). Both d-amphetamine and levodopa are thus potent drugs in enhancing learning in humans. We here discuss why the efficiency of both d-amphetamine and levodopa may be related to dopaminergic rather than noradrenergic actions. PMID:16815467

  18. Noradrenergic modulation of the parallel fiber-Purkinje cell synapse in mouse cerebellum.

    PubMed

    Lippiello, Pellegrino; Hoxha, Eriola; Volpicelli, Floriana; Lo Duca, Giuseppina; Tempia, Filippo; Miniaci, Maria Concetta

    2015-02-01

    The signals arriving to Purkinje cells via parallel fibers are essential for all tasks in which the cerebellum is involved, including motor control, learning new motor skills and calibration of reflexes. Since learning also requires the activation of adrenergic receptors, we investigated the effects of adrenergic receptor agonists on the main plastic site of the cerebellar cortex, the parallel fiber-Purkinje cell synapse. Here we show that noradrenaline serves as an endogenous ligand for both α1-and α2-adrenergic receptors to produce synaptic depression between parallel fibers and Purkinje cells. On the contrary, PF-EPSCs were potentiated by the β-adrenergic receptor agonist isoproterenol. This short-term potentiation was postsynaptically expressed, required protein kinase A, and was mimicked by the β2-adrenoceptor agonist clenbuterol, suggesting that the β2-adrenoceptors mediate the noradrenergic facilitation of synaptic transmission between parallel fibers and Purkinje cells. Moreover, β-adrenoceptor activation lowered the threshold for cerebellar long-term potentiation induced by 1 Hz parallel fiber stimulation. The presence of both α and β adrenergic receptors on Purkinje cells suggests the existence of bidirectional mechanisms of regulation allowing the noradrenergic afferents to refine the signals arriving to Purkinje cells at particular arousal states or during learning. PMID:25218865

  19. Forebrain glucocorticoid receptor gene deletion attenuates behavioral changes and antidepressant responsiveness during chronic stress.

    PubMed

    Jacobson, Lauren

    2014-10-01

    Stress is an important risk factor for mood disorders. Stress also stimulates the secretion of glucocorticoids, which have been found to influence mood. To determine the role of forebrain glucocorticoid receptors (GR) in behavioral responses to chronic stress, the present experiments compared behavioral effects of repeated social defeat in mice with forebrain GR deletion and in floxed GR littermate controls. Repeated defeat produced alterations in forced swim and tail suspension immobility in floxed GR mice that did not occur in mice with forebrain GR deletion. Defeat-induced changes in immobility in floxed GR mice were prevented by chronic antidepressant treatment, indicating that these behaviors were dysphoria-related. In contrast, although mice with forebrain GR deletion exhibited antidepressant-induced decreases in tail suspension immobility in the absence of stress, this response did not occur in mice with forebrain GR deletion after defeat. There were no marked differences in plasma corticosterone between genotypes, suggesting that behavioral differences depended on forebrain GR rather than on abnormal glucocorticoid secretion. Defeat-induced gene expression of the neuronal activity marker c-fos in the ventral hippocampus, paraventricular thalamus and lateral septum correlated with genotype-related differences in behavioral effects of defeat, whereas c-fos induction in the nucleus accumbens and central and basolateral amygdala correlated with genotype-related differences in behavioral responses to antidepressant treatment. The dependence of both negative (dysphoria-related) and positive (antidepressant-induced) behaviors on forebrain GR is consistent with the contradictory effects of glucocorticoids on mood, and implicates these or other forebrain regions in these effects. PMID:25168761

  20. Forebrain glucocorticoid receptor gene deletion attenuates behavioral changes and antidepressant responsiveness during chronic stress

    PubMed Central

    Jacobson, Lauren

    2014-01-01

    Stress is an important risk factor for mood disorders. Stress also stimulates the secretion of glucocorticoids, which have been found to influence mood. To determine the role of forebrain glucocorticoid receptors (GR) in behavioral responses to chronic stress, the present experiments compared behavioral effects of repeated social defeat in mice with forebrain GR deletion and in floxed GR littermate controls. Repeated defeat produced alterations in forced swim and tail suspension immobility in floxed GR mice that did not occur in mice with forebrain GR deletion. Defeat-induced changes in immobility in floxed GR mice were prevented by chronic antidepressant treatment, indicating that these behaviors were dysphoria-related. In contrast, although mice with forebrain GR deletion exhibited antidepressant-induced decreases in tail suspension immobility in the absence of stress, this response did not occur in mice with forebrain GR deletion after defeat. There were no marked differences in plasma corticosterone between genotypes, suggesting that behavioral differences depended on forebrain GR rather than on abnormal glucocorticoid secretion. Defeat-induced gene expression of the neuronal activity marker c-fos in the ventral hippocampus, paraventricular thalamus and lateral septum correlated with genotype-related differences in behavioral effects of defeat, whereas c-fos induction in the nucleus accumbens and central and basolateral amygdala correlated with genotype-related differences in behavioral responses to antidepressant treatment. The dependence of both negative (dysphoria-related) and positive (antidepressant-induced) behaviors on forebrain GR is consistent with the contradictory effects of glucocorticoids on mood, and implicates these or other forebrain regions in these effects. PMID:25168761

  1. From pluripotency to forebrain patterning: an in vitro journey astride embryonic stem cells.

    PubMed

    Lupo, Giuseppe; Bertacchi, Michele; Carucci, Nicoletta; Augusti-Tocco, Gabriella; Biagioni, Stefano; Cremisi, Federico

    2014-08-01

    Embryonic stem cells (ESCs) have been used extensively as in vitro models of neural development and disease, with special efforts towards their conversion into forebrain progenitors and neurons. The forebrain is the most complex brain region, giving rise to several fundamental structures, such as the cerebral cortex, the hypothalamus, and the retina. Due to the multiplicity of signaling pathways playing different roles at distinct times of embryonic development, the specification and patterning of forebrain has been difficult to study in vivo. Research performed on ESCs in vitro has provided a large body of evidence to complement work in model organisms, but these studies have often been focused more on cell type production than on cell fate regulation. In this review, we systematically reassess the current literature in the field of forebrain development in mouse and human ESCs with a focus on the molecular mechanisms of early cell fate decisions, taking into consideration the specific culture conditions, exogenous and endogenous molecular cues as described in the original studies. The resulting model of early forebrain induction and patterning provides a useful framework for further studies aimed at reconstructing forebrain development in vitro for basic research or therapy. PMID:24643740

  2. Neuronal activities of forebrain structures with respect to bladder contraction in cats.

    PubMed

    Yamamoto, Tatsuya; Sakakibara, Ryuji; Nakazawa, Ken; Uchiyama, Tomoyuki; Shimizu, Eiji; Hattori, Takamichi; Kuwabara, Satoshi

    2010-03-31

    The forebrain is one of the important suprapontine micturition centres. Previous studies have shown that electrical stimulation of the frontal lobe and the anterior cingulate gyrus elicited either inhibition or facilitation of bladder contraction. Patients with frontal lobe tumours and aneurysms showed micturition disorders. Functional brain imaging studies showed that several parts of the forebrain are activated during bladder filling. We aimed to examine neuronal activities of forebrain structures with respect to bladder contraction in cats. In 14 adult male cats under ketamine anaesthesia in which a spontaneous isovolumetric bladder-contraction/relaxation cycle had been generated, we carried out extracellular single-unit recording in forebrain with respect to the contraction/relaxation cycles in the bladder. We recorded 112 neurons that were related to the bladder-contraction/relaxation cycles. Ninety-four neurons were found to be tonically activated during the bladder-relaxation phase, whereas the remaining 18 neurons were tonically activated during the bladder-contraction phase. Both types of neuron were widely distributed around the cruciate sulcus. Most were located medially (medial and superior frontal gyrus) and the rest were located laterally (middle and inferior frontal gyrus). Neurons recorded in forebrain structures were activated with respect to the contraction/relaxation cycles in the bladder. Forebrain structures may have a significant role in regulating bladder contraction in cats. PMID:20153810

  3. Roof plate mediated morphogenesis of the forebrain: New players join the game.

    PubMed

    Gupta, Sandeep; Sen, Jonaki

    2016-05-15

    The roof plate is a crucial signaling center located at the dorsal midline of the developing central nervous system (CNS) along its rostro-caudal axis. By virtue of secreting multiple signaling molecules, it regulates diverse processes such as specification of dorsal fate, proliferation and axon guidance. In the forebrain, the roof plate is not only involved in patterning but is also involved in the division of the single forebrain vesicle into the two cerebral hemispheres, the failure of which leads to certain forms of holoprosencephaly. Although several molecular players such as Fgfs, BMPs, Wnts and Shh have been identified as crucial regulators of development of the forebrain, little is known about how they interact to bring about the morphological changes associated with the division of the forebrain vesicle into the cerebral hemispheres. Recent studies have now identified the dorsal mesenchyme as an additional source of signaling cues, which is likely to influence the division of the forebrain vesicle into cerebral hemispheres. In this review, we discuss the current understanding about the molecular mechanisms of roof plate mediated patterning and morphogenesis of the forebrain including some recently identified factors that influence this process and also highlight the gaps in our knowledge that remain. PMID:27012761

  4. Lesions of the Basal Forebrain Cholinergic System in Mice Disrupt Idiothetic Navigation

    PubMed Central

    Hamlin, Adam S.; Windels, Francois; Boskovic, Zoran; Sah, Pankaj; Coulson, Elizabeth J.

    2013-01-01

    Loss of integrity of the basal forebrain cholinergic neurons is a consistent feature of Alzheimer’s disease, and measurement of basal forebrain degeneration by magnetic resonance imaging is emerging as a sensitive diagnostic marker for prodromal disease. It is also known that Alzheimer’s disease patients perform poorly on both real space and computerized cued (allothetic) or uncued (idiothetic) recall navigation tasks. Although the hippocampus is required for allothetic navigation, lesions of this region only mildly affect idiothetic navigation. Here we tested the hypothesis that the cholinergic medial septo-hippocampal circuit is important for idiothetic navigation. Basal forebrain cholinergic neurons were selectively lesioned in mice using the toxin saporin conjugated to a basal forebrain cholinergic neuronal marker, the p75 neurotrophin receptor. Control animals were able to learn and remember spatial information when tested on a modified version of the passive place avoidance test where all extramaze cues were removed, and animals had to rely on idiothetic signals. However, the exploratory behaviour of mice with cholinergic basal forebrain lesions was highly disorganized during this test. By contrast, the lesioned animals performed no differently from controls in tasks involving contextual fear conditioning and spatial working memory (Y maze), and displayed no deficits in potentially confounding behaviours such as motor performance, anxiety, or disturbed sleep/wake cycles. These data suggest that the basal forebrain cholinergic system plays a specific role in idiothetic navigation, a modality that is impaired early in Alzheimer’s disease. PMID:23320088

  5. Maternal sensitivity, infant limbic structure volume and functional connectivity: a preliminary study

    PubMed Central

    Rifkin-Graboi, A; Kong, L; Sim, L W; Sanmugam, S; Broekman, B F P; Chen, H; Wong, E; Kwek, K; Saw, S-M; Chong, Y-S; Gluckman, P D; Fortier, M V; Pederson, D; Meaney, M J; Qiu, A

    2015-01-01

    Mechanisms underlying the profound parental effects on cognitive, emotional and social development in humans remain poorly understood. Studies with nonhuman models suggest variations in parental care affect the limbic system, influential to learning, autobiography and emotional regulation. In some research, nonoptimal care relates to decreases in neurogenesis, although other work suggests early-postnatal social adversity accelerates the maturation of limbic structures associated with emotional learning. We explored whether maternal sensitivity predicts human limbic system development and functional connectivity patterns in a small sample of human infants. When infants were 6 months of age, 20 mother–infant dyads attended a laboratory-based observational session and the infants underwent neuroimaging at the same age. After considering age at imaging, household income and postnatal maternal anxiety, regression analyses demonstrated significant indirect associations between maternal sensitivity and bilateral hippocampal volume at six months, with the majority of associations between sensitivity and the amygdala demonstrating similar indirect, but not significant results. Moreover, functional analyses revealed direct associations between maternal sensitivity and connectivity between the hippocampus and areas important for emotional regulation and socio-emotional functioning. Sensitivity additionally predicted indirect associations between limbic structures and regions related to autobiographical memory. Our volumetric results are consistent with research indicating accelerated limbic development in response to early social adversity, and in combination with our functional results, if replicated in a larger sample, may suggest that subtle, but important, variations in maternal care influence neuroanatomical trajectories important to future cognitive and emotional functioning. PMID:26506054

  6. [A case report of recurrent limbic encephalitis caused by an enterovirus infection].

    PubMed

    Hokezu, Youichi; Hashiguchi, Yoshiya; Satake, Marie; Hosoya, Mitsuaki

    2004-03-01

    We reported a 28-year-old woman with recurrent focal encephalitis caused by an enterovirus infection. She showed convulsions, abnormal behavior, and consciousness disturbance on the first admission to our hospital in July 1998. A CSF study revealed lymphocyte-dominant pleocytosis (17/microl), and brain MRI revealed high signal intensity in the bilateral limbic system including the hippocampus. We treated her with acyclovir and steroid pulse therapy based on a diagnosis of limbic encephalitis. After that, her symptoms gradually disappeared without any sequelae. She became aware of memory disturbance at the end of April 2001. She was admitted to our hospital because of generalized convulsions on 2 May 2001. Her body temperature was 37.3 degrees C. Her consciousness was disturbed (Japan coma scale 2), but there was no nuchal rigidity. A CSF study failed to reveal pleocytosis (cell count, 2/microl). Brain MRI revealed a bilateral high signal intensity area in the limbic system. Her symptoms gradually improved, but the mild memory disturbance persisted on her discharge. An immunological study revealed no abnormality in either humoral or cell immunity. RT-PCR revealed enterovirus RNA in CSF samples obtained on 1 July 1998, 3 May 2001, and 25 July 2001. We diagnosed her as having recurrent limbic encephalitis caused by an enterovirus infection. This is the first report of recurrent limbic encepalitis caused by enterovirus infection in an host with an undetected defect of immune system. PMID:15233268

  7. Maternal sensitivity, infant limbic structure volume and functional connectivity: a preliminary study.

    PubMed

    Rifkin-Graboi, A; Kong, L; Sim, L W; Sanmugam, S; Broekman, B F P; Chen, H; Wong, E; Kwek, K; Saw, S-M; Chong, Y-S; Gluckman, P D; Fortier, M V; Pederson, D; Meaney, M J; Qiu, A

    2015-01-01

    Mechanisms underlying the profound parental effects on cognitive, emotional and social development in humans remain poorly understood. Studies with nonhuman models suggest variations in parental care affect the limbic system, influential to learning, autobiography and emotional regulation. In some research, nonoptimal care relates to decreases in neurogenesis, although other work suggests early-postnatal social adversity accelerates the maturation of limbic structures associated with emotional learning. We explored whether maternal sensitivity predicts human limbic system development and functional connectivity patterns in a small sample of human infants. When infants were 6 months of age, 20 mother-infant dyads attended a laboratory-based observational session and the infants underwent neuroimaging at the same age. After considering age at imaging, household income and postnatal maternal anxiety, regression analyses demonstrated significant indirect associations between maternal sensitivity and bilateral hippocampal volume at six months, with the majority of associations between sensitivity and the amygdala demonstrating similar indirect, but not significant results. Moreover, functional analyses revealed direct associations between maternal sensitivity and connectivity between the hippocampus and areas important for emotional regulation and socio-emotional functioning. Sensitivity additionally predicted indirect associations between limbic structures and regions related to autobiographical memory. Our volumetric results are consistent with research indicating accelerated limbic development in response to early social adversity, and in combination with our functional results, if replicated in a larger sample, may suggest that subtle, but important, variations in maternal care influence neuroanatomical trajectories important to future cognitive and emotional functioning. PMID:26506054

  8. Exendin-4 reverts behavioural and neurochemical dysfunction in a pre-motor rodent model of Parkinson's disease with noradrenergic deficit.

    PubMed

    Rampersaud, N; Harkavyi, A; Giordano, G; Lever, R; Whitton, J; Whitton, Ps

    2012-12-01

    BACKGROUND AND PURPOSE Parkinson's disease (PD) is characterized by progressive dopaminergic cell loss; however, the noradrenergic system exhibits degeneration as well. Noradrenergic deficit in PD may be responsible for certain non-motor symptoms of the pathology, including psychiatric disorders and cognitive decline. The aim of this study was to generate a pre-motor rodent model of PD with noradrenergic denervation, and to assess whether treatment with exendin-4 (EX-4), a glucagon-like peptide 1 receptor agonist, could reverse impairment exhibited by our model. EXPERIMENTAL APPROACH We generated a model of PD utilizing N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine and 6-hydroxydopamine to create partial lesions of both the noradrenergic and dopaminergic systems respectively. We then assessed the validity of our model using an array of behavioural paradigms and biochemical techniques. Finally, we administered EX-4 over a 1 week period to determine therapeutic efficacy. KEY RESULTS Our model exhibits anhedonia and decreased object recognition as indicated by a decrease in sucrose preference, increased immobility in the forced swim test and reduced novel object exploration. Tissue and extracellular dopamine and noradrenaline were reduced in the frontal cortex and striatum. TH+ cell counts decreased in the locus coeruleus and substantia nigra. Treatment with EX-4 reversed behavioural impairment and restored extracellular/tissue levels of both dopamine and noradrenaline and TH+ cell counts. CONCLUSION AND IMPLICATIONS We conclude that early treatment with EX-4 may reverse certain neuropsychiatric dysfunction and restore dopamine and noradrenaline content. PMID:22774922

  9. Both a Nicotinic Single Nucleotide Polymorphism (SNP) and a Noradrenergic SNP Modulate Working Memory Performance when Attention Is Manipulated

    ERIC Educational Resources Information Center

    Greenwood, Pamela M.; Sundararajan, Ramya; Lin, Ming-Kuan; Kumar, Reshma; Fryxell, Karl J.; Parasuraman, Raja

    2009-01-01

    We investigated the relation between the two systems of visuospatial attention and working memory by examining the effect of normal variation in cholinergic and noradrenergic genes on working memory performance under attentional manipulation. We previously reported that working memory for location was impaired following large location precues,…

  10. Habituation and extinction of fear recruit overlapping forebrain structures.

    PubMed

    Furlong, Teri M; Richardson, Rick; McNally, Gavan P

    2016-02-01

    Establishing the neurocircuitry involved in inhibiting fear is important for understanding and treating anxiety disorders. To date, extinction procedures have been predominately used to examine the inhibition of learned fear, where fear is reduced to a conditioned stimulus (CS) by presenting it in the absence of the unconditioned stimulus (US). However, learned fear can also be reduced by habituation procedures where the US is presented in the absence of the CS. Here we used expression of the activity marker c-Fos in rats to compare the recruitment of several forebrain structures following fear habituation and extinction. Following fear conditioning where a tone CS was paired with a loud noise US, fear was then reduced the following day by either presentation of the CS or US alone (i.e. CS extinction or US habituation, respectively). This extinction and habituation training recruited several common structures, including infralimbic cortex, basolateral amygdala, midline thalamus and medial hypothalamus (orexin neurons). Moreover, this overlap was shared when examining the neural correlates of the expression of habituation and extinction, with common recruitment of infralimbic cortex and midline thalamus. However, there were also important differences. Specifically, acquisition of habituation was associated with greater recruitment of prelimbic cortex whereas expression of habituation was associated with greater recruitment of paraventricular thalamus. There was also less recruitment of central amygdala for habituation compared to extinction in the retention phase. These findings indicate that largely overlapping neurocircuitries underlie habituation and fear extinction and imply common mechanisms for reducing fear across different inhibitory treatments. PMID:26690954

  11. Molecular Diversity Subdivides the Adult Forebrain Neural Stem Cell Population

    PubMed Central

    Giachino, Claudio; Basak, Onur; Lugert, Sebastian; Knuckles, Philip; Obernier, Kirsten; Fiorelli, Roberto; Frank, Stephan; Raineteau, Olivier; Alvarez–Buylla, Arturo; Taylor, Verdon

    2014-01-01

    Neural stem cells (NSCs) in the ventricular domain of the subventricular zone (V-SVZ) of rodents produce neurons throughout life while those in humans become largely inactive or may be lost during infancy. Most adult NSCs are quiescent, express glial markers, and depend on Notch signaling for their self-renewal and the generation of neurons. Using genetic markers and lineage tracing, we identified subpopulations of adult V-SVZ NSCs (type 1, 2, and 3) indicating a striking heterogeneity including activated, brain lipid binding protein (BLBP, FABP7) expressing stem cells. BLBP+ NSCs are mitotically active components of pinwheel structures in the lateral ventricle walls and persistently generate neurons in adulthood. BLBP+ NSCs express epidermal growth factor (EGF) receptor, proliferate in response to EGF, and are a major clonogenic population in the SVZ. We also find BLBP expressed by proliferative ventricular and sub-ventricular progenitors in the fetal and postnatal human brain. Loss of BLBP+ stem/progenitor cells correlates with reduced neurogenesis in aging rodents and postnatal humans. These findings of molecular heterogeneity and proliferative differences subdivide the NSC population and have implications for neurogenesis in the forebrain of mammals during aging. PMID:23964022

  12. Evolution and development of interhemispheric connections in the vertebrate forebrain

    PubMed Central

    Suárez, Rodrigo; Gobius, Ilan; Richards, Linda J.

    2014-01-01

    Axonal connections between the left and right sides of the brain are crucial for bilateral integration of lateralized sensory, motor, and associative functions. Throughout vertebrate species, forebrain commissures share a conserved developmental plan, a similar position relative to each other within the brain and similar patterns of connectivity. However, major events in the evolution of the vertebrate brain, such as the expansion of the telencephalon in tetrapods and the origin of the six-layered isocortex in mammals, resulted in the emergence and diversification of new commissural routes. These new interhemispheric connections include the pallial commissure, which appeared in the ancestors of tetrapods and connects the left and right sides of the medial pallium (hippocampus in mammals), and the corpus callosum, which is exclusive to eutherian (placental) mammals and connects both isocortical hemispheres. A comparative analysis of commissural systems in vertebrates reveals that the emergence of new commissural routes may have involved co-option of developmental mechanisms and anatomical substrates of preexistent commissural pathways. One of the embryonic regions of interest for studying these processes is the commissural plate, a portion of the early telencephalic midline that provides molecular specification and a cellular scaffold for the development of commissural axons. Further investigations into these embryonic processes in carefully selected species will provide insights not only into the mechanisms driving commissural evolution, but also regarding more general biological problems such as the role of developmental plasticity in evolutionary change. PMID:25071525

  13. Dopamine receptor gene expression by enkephalin neurons in rat forebrain

    SciTech Connect

    Le Moine, C.; Normand, E.; Guitteny, A.F.; Fouque, B.; Teoule, R.; Bloch, B. )

    1990-01-01

    In situ hybridization experiments were performed with brain sections from normal, control and haloperidol-treated rats to identify and map the cells expressing the D2 dopamine receptor gene. D2 receptor mRNA was detected with radioactive or biotinylated oligonucleotide probes. D2 receptor mRNA was present in glandular cells of the pituitary intermediate lobe and in neurons of the substantia nigra, ventral tegmental area, and forebrain, especially in caudate putamen, nucleus accumbens, olfactory tubercle, and piriform cortex. Hybridization with D2 and preproenkephalin A probes in adjacent sections, as well as combined hybridization with the two probes in the same sections, demonstrated that all detectable enkephalin neurons in the striatum contained the D2 receptor mRNA. Large neurons in caudate putamen, which were unlabeled with the preproenkephalin A probe and which may have been cholinergic, also expressed the D2 receptor gene. Haloperidol treatment (14 or 21 days) provoked an increase in mRNA content for D2 receptor and preproenkephalin A in the striatum. This suggests that the increase in D2 receptor number observed after haloperidol treatment is due to increased activity of the D2 gene. These results indicate that in the striatum, the enkephalin neurons are direct targets for dopamine liberated from mesostriatal neurons.

  14. Subregional Basal Forebrain Atrophy in Alzheimer's Disease: A Multicenter Study

    PubMed Central

    Kilimann, Ingo; Grothe, Michel; Heinsen, Helmut; Alho, Eduardo Joaquim Lopez; Grinberg, Lea; Amaro, Edson; dos Santos, Gláucia Aparecida Bento; da Silva, Rafael Emídio; Mitchell, Alex J.; Frisoni, Giovanni B.; Bokde, Arun L.W.; Fellgiebel, Andreas; Filippi, Massimo; Hampel, Harald; Klöppel, Stefan; Teipel, Stefan J.

    2014-01-01

    Histopathological studies in Alzheimer's disease (AD) suggest severe and region-specific neurodegeneration of the basal forebrain cholinergic system (BFCS). Here, we studied the between-center reliability and diagnostic accuracy of MRI-based BFCS volumetry in a large multicenter data set, including participants with prodromal (n = 41) or clinically manifest AD (n = 134) and 148 cognitively healthy controls. Atrophy was determined using voxel-based and region-of-interest based analyses of high-dimensionally normalized MRI scans using a newly created map of the BFCS based on postmortem in cranio MRI and histology. The AD group showed significant volume reductions of all subregions of the BFCS, which were most pronounced in the posterior nucleus basalis Meynert (NbM). The mild cognitive impairment-AD group showed pronounced volume reductions in the posterior NbM, but preserved volumes of anterior-medial regions. Diagnostic accuracy of posterior NbM volume was superior to hippocampus volume in both groups, despite higher multicenter variability of the BFCS measurements. The data of our study suggest that BFCS morphometry may provide an emerging biomarker in AD. PMID:24503619

  15. Forebrain neurocircuitry associated with human reflex cardiovascular control

    PubMed Central

    Shoemaker, J. Kevin; Goswami, Ruma

    2015-01-01

    Physiological homeostasis depends upon adequate integration and responsiveness of sensory information with the autonomic nervous system to affect rapid and effective adjustments in end organ control. Dysregulation of the autonomic nervous system leads to cardiovascular disability with consequences as severe as sudden death. The neural pathways involved in reflexive autonomic control are dependent upon brainstem nuclei but these receive modulatory inputs from higher centers in the midbrain and cortex. Neuroimaging technologies have allowed closer study of the cortical circuitry related to autonomic cardiovascular adjustments to many stressors in awake humans and have exposed many forebrain sites that associate strongly with cardiovascular arousal during stress including the medial prefrontal cortex, insula cortex, anterior cingulate, amygdala and hippocampus. Using a comparative approach, this review will consider the cortical autonomic circuitry in rodents and primates with a major emphasis on more recent neuroimaging studies in awake humans. A challenge with neuroimaging studies is their interpretation in view of multiple sensory, perceptual, emotive and/or reflexive components of autonomic responses. This review will focus on those responses related to non-volitional baroreflex control of blood pressure and also on the coordinated responses to non-fatiguing, non-painful volitional exercise with particular emphasis on the medial prefrontal cortex and the insula cortex. PMID:26388780

  16. Stimulation of the noradrenergic system during memory formation impairs extinction learning but not the disruption of reconsolidation.

    PubMed

    Soeter, Marieke; Kindt, Merel

    2012-04-01

    The noradrenergic system plays a critical role in the 'consolidation' of emotional memory. If we are to target 'reconsolidation' in patients with anxiety disorders, the noradrenergic strengthening of fear memory should not impair the disruption of reconsolidation. In Experiment I, we addressed this issue using a differential fear conditioning procedure allowing selective reactivation of one of two fear associations. First, we strengthened fear memory by administering an α(2)-adrenergic receptor antagonist (ie, yohimbine HCl; double-blind placebo-controlled study) 30 min before acquisition (time for peak value yohimbine HCl <1 h). Next, the reconsolidation of one of the fear associations was manipulated by administering a β-adrenergic receptor antagonist (ie, propranolol HCl) 90 min before its selective reactivation (time for peak value propranolol HCl <2 h). In Experiment II, we administered propranolol HCl after reactivation of the memory to rule out a possible effect of the pharmacological manipulation on the memory retrieval itself. The excessive release of noradrenaline during memory formation not only delayed the process of extinction 48 h later, but also triggered broader fear generalization. Yet, the β-adrenergic receptor blocker during reconsolidation selectively 'neutralized' the fear-arousing aspects of the noradrenergic-strengthened memory and undermined the generalization of fear. We observed a similar reduction in fear responding when propranolol HCl was administered after reactivation of the memory. The present findings demonstrate the involvement of noradrenergic modulation in the formation as well as generalization of human fear memory. Given that the noradrenergic strengthening of fear memory impaired extinction learning but not the disruption of reconsolidation, our findings may have implications for the treatment of anxiety disorders. PMID:22169947

  17. Ilex paraguariensis Promotes Orofacial Pain Relief After Formalin Injection: Involvement of Noradrenergic Pathway

    PubMed Central

    de Carvalho, Eudislaine Fonseca; de Oliveira, Simone Kobe; Nardi, Viviane Koepp; Gelinski, Tathiana Carla; Bortoluzzi, Marcelo Carlos; Maraschin, Marcelo; Nardi, Geisson Marcos

    2016-01-01

    Background: Drinking mate or chimarrão, a hot infusion of Ilex paraguariensis (ILEX) leaves, is a common habit in Southern South America that has a social and almost ritualistic role. It has been used as a stimulant beverage in South America and analgesic in regions of Argentina for treatment of headache and others painful inflammatory conditions such as arthritis and rheumatism. Objective: The aim of this study was to evaluate the pharmacological activity of I. paraguariensis infusion (ILEX) on orofacial nociception model induced by formalin, and study its mechanism of action. Materials and Methods: The analgesic effect of ILEX was assessed through writhing test, paw formalin test, paw edema induced by carrageenan, and orofacial pain induced by formalin. To study the action mechanism of ILEX, opioidergic, dopaminergic, nitrergic, and adrenergic pathways were investigated. Results: The high-performance liquid chromatography analysis of ILEX infusion revealed caffeine and theobromine. The treatment with ILEX reduced the number of writhing. However, it was effective neither in the formalin paw test nor in the paw edema induced by carrageenan. Different from formalin paw test, ILEX was able to reduce the orofacial reactivity to formalin in 31.8% (70.4 ± 2.5 s; first phase), and 20% (127.3 ± 18.9 s; second phase). The analgesic effect of ILEX results from the modulation of noradrenergic pathways since prazosin (α1-adrenoceptor antagonist, 0.15 mg/kg; intraperitoneal) reversed the analgesic effect of ILEX. Conclusions: The present report demonstrates that analgesic effect of ILEX in orofacial formalin test is due mainly to modulation of noradrenergic pathways. SUMMARY Ilex paraguariensis (ILEX) has been used as a stimulant beverage in South America and analgesic in regions of Argentina for the treatment of headache and others painful inflammatory conditions such arthritis and rheumatism.The aim of this study was to evaluate the pharmacological activity of ILEX on

  18. Limbic Encephalitis: Potential Impact of Adaptive Autoimmune Inflammation on Neuronal Circuits of the Amygdala.

    PubMed

    Melzer, Nico; Budde, Thomas; Stork, Oliver; Meuth, Sven G

    2015-01-01

    Limbic encephalitis is characterized by adaptive autoimmune inflammation of the gray matter structures of the limbic system. It has recently been identified as a major cause of temporal lobe epilepsy accompanied by progressive declarative - mainly episodic - -memory disturbance as well as a variety of rather poorly defined emotional and behavioral changes. While autoimmune inflammation of the hippocampus is likely to be responsible for declarative memory disturbance, consequences of autoimmune inflammation of the amygdala are largely unknown. The amygdala is central for the generation of adequate homoeostatic behavioral responses to emotionally significant external stimuli following processing in a variety of parallel neuronal circuits. Here, we hypothesize that adaptive cellular and humoral autoimmunity may target and modulate distinct inhibitory or excitatory neuronal networks within the amygdala, and thereby strongly impact processing of emotional stimuli and corresponding behavioral responses. This may explain some of the rather poorly understood neuropsychiatric symptoms in limbic encephalitis. PMID:26284026

  19. Sexually dimorphic effects of the Lhx7 null mutation on forebrain cholinergic function.

    PubMed

    Fragkouli, A; Stamatakis, A; Zographos, E; Pachnis, V; Stylianopoulou, F

    2006-01-01

    It has been reported recently that mice lacking both alleles of the LIM-homeobox gene Lhx7, display dramatically reduced number of forebrain cholinergic neurons. In the present study, we investigated whether the Lhx7 mutation affects male and female mice differently, given the fact that gender differences are consistently observed in forebrain cholinergic function. Our results show that in adult male as well as female Lhx7 homozygous mutants there is a dramatic loss of choline acetyltransferase immunoreactive forebrain neurons, both projection and interneurons. The reduction of forebrain choline acetyltransferase immunoreactive neurons in Lhx7 homozygous mutants is accompanied by a decrease of acetylcholinesterase histochemical staining in all forebrain cholinergic neuron target areas of both male and female homozygous mutants. Furthermore, there was an increase of M1-, but not M2-, muscarinic acetylcholine receptor binding site density in the somatosensory cortex and basal ganglia of only the female homozygous mutant mice. Such an increase can be regarded as a mechanism acting to compensate for the dramatically reduced cholinergic input, raising the possibility that the forebrain cholinergic system in female mice may be more plastic and responsive to situations of limited neurotransmitter availability. Finally, our study provides additional data for the sexual dimorphism of the forebrain cholinergic system, as female mice appear to have a lower density of M1-muscarinic acetylcholine receptors in the striatal areas of the basal ganglia and a higher density of M2-muscarinic acetylcholine receptors, in a number of cortical areas, as well as the striatal areas of the basal ganglia. PMID:16338089

  20. Paraneoplastic limbic encephalitis and possible narcolepsy in a patient with testicular cancer: case study.

    PubMed Central

    Landolfi, Joseph C.; Nadkarni, Mangala

    2003-01-01

    We describe a patient who presented with a clinical syndrome of limbic encephalitis, narcolepsy, and cataplexy. The anti-Ma2 antibody was positive. Although there was no mass on imaging, orchiectomy was performed in this patient, and testicular carcinoma was found. This is the first known case of limbic encephalitis and anti-Ma2 antibody to be associated with cataplexy and possible narcolepsy. Neurological symptoms precede the diagnosis of cancer in 50% of patients with paraneoplastic syndromes, and clinicians are therefore strongly advised to evaluate patients with neurological symptoms for this condition. PMID:12816728

  1. LEVOMILNACIPRAN--A SUCCESSOR OF MILNACIPRAN WITH A HIGHER NORADRENERGIC SELECTIVITY.

    PubMed

    Zadka, Łukasz; Dziwota, Ewelina; Olajossy, Marcin

    2016-01-01

    A new antidepressant, levomilnacipran, is the levorotatory enantiomer of milnacipran. The drug belongs to selective serotonin-norepinephrine reuptake inhibitors (SNRI) and has the highest noradrenergic selectivity of all members of this group of antidepressants. Clinical trials have confirmed the effectiveness of levomilnacipran in the treatment of depression. The drug was placed on the US market in the form of prolonged-release capsules, which greatly simplifies the treatment of psychiatric patients. The safety of the drug is also higher than the safety of a racemate, resulting in a beneficial impact on the therapeutic effect. In this paper we present current information on the pharmacological and clinical properties of the newest antidepressant--levomilnacipran. PMID:27180420

  2. Coordinated forms of noradrenergic plasticity in the locus coeruleus and primary auditory cortex

    PubMed Central

    Martins, Ana Raquel O.; Froemke, Robert C.

    2015-01-01

    The cerebral cortex is plastic and represents the world according to the significance of sensory stimuli. However, cortical networks are embodied within complex circuits including neuromodulatory systems such as the noradrenergic locus coeruleus, providing information about internal state and behavioral relevance. While norepinephrine is important for cortical plasticity, it is unknown how modulatory neurons themselves respond to changes of sensory input. Here we examine how locus coeruleus neurons are modified by experience, and the consequences of locus coeruleus plasticity on cortical representations and sensory perception. We made whole-cell recordings from rat locus coeruleus and primary auditory cortex (AI), pairing sounds with locus coeruleus activation. Although initially unresponsive, locus coeruleus neurons developed and maintained auditory responses afterwards. Locus coeruleus plasticity induced changes in AI responses lasting at least hours and improved auditory perception for days to weeks. Our results demonstrate that locus coeruleus is highly plastic, leading to substantial changes in regulation of brain state by norepinephrine. PMID:26301326

  3. Thermoregulatory effects of chlorpyrifos in the rat: long-term changes in cholinergic and noradrenergic sensitivity.

    PubMed

    Gordon, C J

    1994-01-01

    Subcutaneous injection of a sublethal dose of chlorpyrifos (CHLP), an organophosphate (OP) pesticide, causes long-term inhibition in cholinesterase activity (ChE) of brain, blood, and other tissues. Such prolonged inhibition in ChE should lead to marked behavioral and autonomic thermoregulatory patterns, especially in terms of altered noradrenergic and cholinergic sensitivity. To evaluate the behavioral and autonomic effects of long-term ChE inhibition, Long-Evans rats were implanted with radiotelemetry transmitters that continuously monitored core temperature (Tc), heart rate (HR), and motor activity (MA). These parameters were monitored for 7 days following a single injection of peanut oil (vehicle control) or 280 mg/kg CHLP. CHLP led to a significant reduction in Tc during the first night after treatment but had no other effects on Tc. CHLP also resulted in a significant elevation in HR which lasted for approximately 72 h. Motor activity was unaffected by CHLP. Cholinergic and noradrenergic drug sensitivity was assessed between 7 and 25 days after CHLP. CHLP-treated rats were more sensitive to norepinephrine as based on a greater hyperthermic response. MA of CHLP-treated rats was more sensitive to scopolamine. On the other hand, the hypothermic effects of oxotremorine (0.4 mg/kg) were nearly abolished by CHLP treatment, indicating tolerance to cholinergic stimulation. The tachycardic effects of methyscopolamine were also greater in the CHLP group. Overall, the acute effects of CHLP are unusual compared to other OP's in that there is no hypothermic response, an attenuated nocturnal elevation in Tc and a prolonged elevation in HR.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7514260

  4. Central antinociceptive effects of mitragynine in mice: contribution of descending noradrenergic and serotonergic systems.

    PubMed

    Matsumoto, K; Mizowaki, M; Suchitra, T; Murakami, Y; Takayama, H; Sakai, S; Aimi, N; Watanabe, H

    1996-12-12

    Mitragynine is a major alkaloidal constituent of young leaves of Mitragyna speciosa Korth, that is known to exhibit narcotic-like activity. In this study, we investigated the roles of central monoaminergic systems in the antinociceptive action of mitragynine by means of the tail-pinch and hot-plate tests in mice. Mitragynine (1.0-10 micrograms) injected i.c.v. exerted a dose-dependent antinociceptive activity in both tests. The activity of mitragynine (10 micrograms, i.c.v.) in the tail-pinch test was antagonized by reserpine, 6-hydroxydopamine plus nomifensine, and p-chlorophenylalnine treatment, whereas the antinociceptive activity of morphine (3 micrograms) given i.c.v. in this test was attenuated by 6-hydroxydopamine plus nomifensine but not by p-chlorophenylalanine treatment. Moreover, the activity of i.c.v. mitragynine was also antagonized by the alpha 2-adrenoceptor antagonist, idazoxan (10 micrograms), and cyproheptadine (1 microgram) administered intrathecally (i.t.). On the other hand, the antinociceptive action of i.c.v. mitragynine (10 micrograms) in the hot-plate test was abolished by reserpine and 6-hydroxydopamine plus nomifensine, but not by p-chlorophenylalanine treatment. This action was also antagonized by i.t. injection of idazoxan (10 micrograms). These results suggest that both descending noradrenergic and serotonergic systems are involved in the antinociceptive activity of supraspinally administered mitragynine on the mechanical noxious stimulation, while the descending noradrenergic system predominantly contributes to the effect of supraspinal mitragynine on the thermal noxious stimulation. The mechanisms underlying the suppressive action of mitragynine on the nociceptive response may differ from those of morphine in mice. PMID:8982722

  5. Bisphenol A exposure disrupts the development of the locus coeruleus-noradrenergic system in mice.

    PubMed

    Tando, So; Itoh, Kyoko; Yaoi, Takeshi; Ogi, Hiroshi; Goto, Shoko; Mori, Miyuki; Fushiki, Shinji

    2014-12-01

    It has been reported that bisphenol A (BPA), a widespread xenoestrogen employed in the production of polycarbonate plastics, affects brain development in both humans and rodents. In the present study employing mice, we examined the effects of exposure to BPA (500 μg/kg/day) during fetal and lactational periods on the development of the locus coeruleus (LC) at the age of embryonic day 18 (E18), postnatal 3 weeks (P3W), P8W and P16W. The number of tyrosine hydroxylase-immunoreactive cells (TH-IR cells) in females exposed to BPA was decreased, compared with the control females at P3W. At P8W, the number of TH-IR cells in females exposed to BPA was significantly decreased, compared with the control females, whereas the number of TH-IR cells in males exposed to BPA was significantly increased, compared with the control males, which resulted in reversed transient sexual differences in the numbers of TH-IR cells observed in the controls at P8W. However, no significant changes were demonstrated at E18 or P16W. Next, we examined the density of the fibers containing norepinephrine transporter (NET) in the anterior cingulate cortex (ACC) and prefrontal cortex, at P3W, P8W and P16W, because NET would be beneficial in identifying the targets of the LC noradrenergic neurons. There were no significant differences shown in the density of the NET-positive fibers, between the control and the groups exposed to BPA. These results suggested that BPA might disrupt the development of physiological sexual differences in the LC-noradrenergic system in mice, although further studies are necessary to clarify the underlying mechanisms. PMID:24985408

  6. CONDITIONAL ABLATION AND RECOVERY OF FOREBRAIN NEUROGENESIS IN THE MOUSE

    PubMed Central

    Singer, Benjamin H.; Jutkiewicz, Emily M.; Fuller, Cynthia L.; Lichtenwalner, Robin J.; Zhang, Helen; Velander, Alan J.; Li, Xiangquan; Gnegy, Margaret E.; Burant, Charles F.; Parent, Jack M.

    2009-01-01

    Forebrain neurogenesis persists throughout life in the rodent subventricular zone (SVZ) and hippocampal dentate gyrus (DG). Several strategies have been employed to eliminate adult neurogenesis and thereby determine whether depleting adult-born neurons disrupts specific brain functions, but some approaches do not specifically target neural progenitors. We have developed a transgenic mouse line to reversibly ablate adult neural stem cells and suppress neurogenesis. The nestin-tk mouse expresses herpes simplex virus thymidine kinase (tk) under the control of the nestin 2nd intronic enhancer, which drives expression in neural progenitors. Administration of ganciclovir (GCV) kills actively dividing cells expressing this transgene. We found that peripheral GCV administration suppressed SVZ-olfactory bulb and DG neurogenesis within two weeks but caused systemic toxicity. Intracerebroventricular GCV infusion for 28 days nearly completely depleted proliferating cells and immature neurons in both the SVZ and DG without systemic toxicity. Reversibility of the effects after prolonged GCV infusion was slow and partial. Neurogenesis did not recover 2 weeks after cessation of GCV administration, but showed limited recovery 6 weeks after GCV that differed between the SVZ and DG. Suppression of neurogenesis did not inhibit antidepressant responsiveness of mice in the tail suspension test. These findings indicate that SVZ and DG neural stem cells differ in their capacity for repopulation, and that adult-born neurons are not required for antidepressant responses in a common behavioral test of antidepressant efficacy. The nestin-tk mouse should be useful for studying how reversible depletion of adult neurogenesis influences neurophysiology, other behaviors, and neural progenitor dynamics. PMID:19363795

  7. Visualization of the medial forebrain bundle using diffusion tensor imaging

    PubMed Central

    Hana, Ardian; Hana, Anisa; Dooms, Georges; Boecher-Schwarz, Hans; Hertel, Frank

    2015-01-01

    Diffusion tensor imaging is a technique that enables physicians the portrayal of white matter tracts in vivo. We used this technique in order to depict the medial forebrain bundle (MFB) in 15 consecutive patients between 2012 and 2015. Men and women of all ages were included. There were six women and nine men. The mean age was 58.6 years (39–77). Nine patients were candidates for an eventual deep brain stimulation. Eight of them suffered from Parkinson‘s disease and one had multiple sclerosis. The remaining six patients suffered from different lesions which were situated in the frontal lobe. These were 2 metastasis, 2 meningiomas, 1 cerebral bleeding, and 1 glioblastoma. We used a 3DT1-sequence for the navigation. Furthermore T2- and DTI- sequences were performed. The FOV was 200 × 200 mm2, slice thickness 2 mm, and an acquisition matrix of 96 × 96 yielding nearly isotropic voxels of 2 × 2 × 2 mm. 3-Tesla-MRI was carried out strictly axial using 32 gradient directions and one b0-image. We used Echo-Planar-Imaging (EPI) and ASSET parallel imaging with an acceleration factor of 2. b-value was 800 s/mm2. The maximal angle was 50°. Additional scanning time was < 9 min. We were able to visualize the MFB in 12 of our patients bilaterally and in the remaining three patients we depicted the MFB on one side. It was the contralateral side of the lesion. These were 2 meningiomas and one metastasis. Portrayal of the MFB is possible for everyday routine for neurosurgical interventions. As part of the reward circuitry it might be of substantial importance for neurosurgeons during deep brain stimulation in patients with psychiatric disorders. Surgery in this part of the brain should always take the preservation of this white matter tract into account. PMID:26581828

  8. Fgf16 Is Required for Specification of GABAergic Neurons and Oligodendrocytes in the Zebrafish Forebrain

    PubMed Central

    Miyake, Ayumi; Chitose, Tatsuya; Kamei, Eriko; Murakami, Atsuko; Nakayama, Yoshiaki; Konishi, Morichika; Itoh, Nobuyuki

    2014-01-01

    Fibroblast growth factor (Fgf) signaling plays crucial roles in various developmental processes including those in the brain. We examined the role of Fgf16 in the formation of the zebrafish brain. The knockdown of fgf16 decreased cell proliferation in the forebrain and midbrain. fgf16 was also essential for development of the ventral telencephalon and diencephalon, whereas fgf16 was not required for dorsoventral patterning in the midbrain. fgf16 was additionally required for the specification and differentiation of γ–aminobutyric acid (GABA)ergic interneurons and oligodendrocytes, but not for those of glutamatergic neurons in the forebrain. Cross talk between Fgf and Hedgehog (Hh) signaling was critical for the specification of GABAergic interneurons and oligodendrocytes. The expression of fgf16 in the forebrain was down-regulated by the inhibition of Hh and Fgf19 signaling, but not by that of Fgf3/Fgf8 signaling. The fgf16 morphant phenotype was similar to that of the fgf19 morphant and embryos blocked Hh signaling. The results of the present study indicate that Fgf16 signaling, which is regulated by the downstream pathways of Hh-Fgf19 in the forebrain, is involved in forebrain development. PMID:25357195

  9. Developmental shifts in gene expression in the auditory forebrain during the sensitive period for song learning

    PubMed Central

    London, Sarah E.; Dong, Shu; Replogle, Kirstin; Clayton, David F.

    2009-01-01

    A male zebra finch begins to learn to sing by memorizing a tutor’s song during a sensitive period in juvenile development. Tutor song memorization requires molecular signaling within the auditory forebrain. Using microarray and in situ hybridizations, we tested whether the auditory forebrain at an age just prior to tutoring expresses a different set of genes compared to later in life after song learning has ceased. Microarray analysis revealed differences in expression of thousands of genes in the male auditory forebrain at posthatch day 20 (P20) compared to adulthood. Further, song playbacks had essentially no impact on gene expression in P20 auditory forebrain, but altered expression of hundreds of genes in adults. Most genes that were song-responsive in adults were expressed at constitutively high levels at P20. Using in situ hybridization with a representative sample of 44 probes, we confirmed these effects and found that birds at P20 and P45 were similar in their gene expression patterns. Additionally, 8 of the probes showed male-female differences in expression. We conclude that the developing auditory forebrain is in a very different molecular state from the adult, despite its relatively mature gross morphology and electrophysiological responsiveness to song stimuli. Developmental gene expression changes may contribute to fine-tuning of cellular and molecular properties necessary for song learning. PMID:19360720

  10. Brain atrophy in primary progressive aphasia involves the cholinergic basal forebrain and Ayala’s nucleus

    PubMed Central

    Teipel, Stefan J.; Flatz, Wilhelm; Ackl, Nibal; Grothe, Michel; Kilimann, Ingo; Bokde, Arun L.W.; Grinberg, Lea; Amaro, Edson; Kljajevic, Vanja; Alho, Eduardo; Knels, Christina; Ebert, Anne; Heinsen, Helmut; Danek, Adrian

    2014-01-01

    Primary progressive aphasia (PPA) is characterized by left hemispheric frontotemporal cortical atrophy. Evidence from anatomical studies suggests that the nucleus subputaminalis (NSP), a subnucleus of the cholinergic basal forebrain, may be involved in the pathological process of PPA. Therefore, we studied the pattern of cortical and basal forebrain atrophy in 10 patients with a clinical diagnosis of PPA and 18 healthy age-matched controls using high-resolution magnetic resonance imaging (MRI). We determined the cholinergic basal forebrain nuclei according to Mesulam’s nomenclature and the NSP in MRI reference space based on histological sections and the MRI scan of a post-mortem brain in cranio. Using voxel-based analysis, we found left hemispheric cortical atrophy in PPA patients compared with controls, including prefrontal, lateral temporal and medial temporal lobe areas. We detected cholinergic basal forebrain atrophy in left predominant localizations of Ch4p, Ch4am, Ch4al, Ch3 and NSP. For the first time, we have described the pattern of basal forebrain atrophy in PPA and confirmed the involvement of NSP that had been predicted based on theoretical considerations. Our findings may enhance understanding of the role of cholinergic degeneration for the regional specificity of the cortical destruction leading to the syndrome of PPA. PMID:24434193

  11. Sox2-mediated differential activation of Six3.2 contributes to forebrain patterning.

    PubMed

    Beccari, Leonardo; Conte, Ivan; Cisneros, Elsa; Bovolenta, Paola

    2012-01-01

    The vertebrate forebrain is patterned during gastrulation into telencephalic, retinal, hypothalamic and diencephalic primordia. Specification of each of these domains requires the concerted activity of combinations of transcription factors (TFs). Paradoxically, some of these factors are widely expressed in the forebrain, which raises the question of how they can mediate regional differences. To address this issue, we focused on the homeobox TF Six3.2. With genomic and functional approaches we demonstrate that, in medaka fish, Six3.2 regulates, in a concentration-dependent manner, telencephalic and retinal specification under the direct control of Sox2. Six3.2 and Sox2 have antagonistic functions in hypothalamic development. These activities are, in part, executed by Foxg1 and Rx3, which seem to be differentially and directly regulated by Six3.2 and Sox2. Together, these data delineate the mechanisms by which Six3.2 diversifies its activity in the forebrain and highlight a novel function for Sox2 as one of the main regulators of anterior forebrain development. They also demonstrate that graded levels of the same TF, probably operating in partially independent transcriptional networks, pattern the vertebrate forebrain along the anterior-posterior axis. PMID:22096077

  12. Compensatory changes in the noradrenergic nervous system in the locus ceruleus and hippocampus of postmortem subjects with Alzheimer's disease and dementia with Lewy bodies.

    PubMed

    Szot, Patricia; White, Sylvia S; Greenup, J Lynne; Leverenz, James B; Peskind, Elaine R; Raskind, Murray A

    2006-01-11

    In Alzheimer's disease (AD), there is a significant loss of locus ceruleus (LC) noradrenergic neurons. However, functional and anatomical evidence indicates that the remaining noradrenergic neurons may be compensating for the loss. Because the noradrenergic system plays an important role in learning and memory, it is important to determine whether compensation occurs in noradrenergic neurons in the LC and hippocampus of subjects with AD or a related dementing disorder, dementia with Lewy bodies (DLB). We observed profound neuronal loss in the LC in AD and DLB subjects with three major changes in the noradrenergic system consistent with compensation: (1) an increase in tyrosine hydroxylase (TH) mRNA expression in the remaining neurons; (2) sprouting of dendrites into peri-LC dendritic zone, as determined by alpha2-adrenoreceptors (ARs) and norepinephrine transporter binding sites; and (3) sprouting of axonal projections to the hippocampus as determined by alpha2-ARs. In AD and DLB subjects, the postsynaptic alpha1-ARs were normal to elevated. Expression of alpha1A- and alpha2A-AR mRNA in the hippocampus of AD and DLB subjects were not altered, but expression of alpha1D- and alpha2C-AR mRNA was significantly reduced in the hippocampus of AD and DLB subjects. Therefore, in AD and DLB subjects, there is compensation occurring in the remaining noradrenergic neurons, but there does appear to be a loss of specific AR in the hippocampus. Because changes in these noradrenergic markers in AD versus DLB subjects were similar (except neuronal loss and the increase in TH mRNA were somewhat greater in DLB subjects), the presence of Lewy bodies in addition to plaques and tangles in DLB subjects does not appear to further affect the noradrenergic compensatory changes. PMID:16407544

  13. Early Life Stress as an Influence on Limbic Epilepsy: An Hypothesis Whose Time has Come?

    PubMed Central

    Koe, Amelia S.; Jones, Nigel C.; Salzberg, Michael R.

    2009-01-01

    The pathogenesis of mesial temporal lobe epilepsy (MTLE), the most prevalent form of refractory focal epilepsy in adults, is thought to begin in early life, even though seizures may not commence until adolescence or adulthood. Amongst the range of early life factors implicated in MTLE causation (febrile seizures, traumatic brain injury, etc.), stress may be one important contributor. Early life stress is an a priori agent deserving study because of the large amount of neuroscientific data showing enduring effects on structure and function in hippocampus and amygdala, the key structures involved in MTLE. An emerging body of evidence directly tests hypotheses concerning early life stress and limbic epilepsy: early life stressors, such as maternal separation, have been shown to aggravate epileptogenesis in both status epilepticus and kindling models of limbic epilepsy. In addition to elucidating its influence on limbic epileptogenesis itself, the study of early life stress has the potential to shed light on the psychiatric disorder that accompanies MTLE. For many years, psychiatric comorbidity was viewed as an effect of epilepsy, mediated psychologically and/or neurobiologically. An alternative – or complementary – perspective is that of shared causation. Early life stress, implicated in the pathogenesis of several psychiatric disorders, may be one such causal factor. This paper aims to critically review the body of experimental evidence linking early life stress and epilepsy; to discuss the direct studies examining early life stress effects in current models of limbic seizures/epilepsy; and to suggest priorities for future research. PMID:19838325

  14. Early life stress modulates oxytocin effects on limbic system during acute psychosocial stress

    PubMed Central

    Pestke, Karin; Feeser, Melanie; Aust, Sabine; Weigand, Anne; Wang, Jue; Wingenfeld, Katja; Pruessner, Jens C.; La Marca, Roberto; Böker, Heinz; Bajbouj, Malek

    2014-01-01

    Early life stress (ELS) is associated with altered stress responsivity, structural and functional brain changes and an increased risk for the development of psychopathological conditions in later life. Due to its behavioral and physiological effects, the neuropeptide oxytocin (OXT) is a useful tool to investigate stress responsivity, even though the neurobiological underpinnings of its effects are still unknown. Here we investigate the effects of OXT on cortisol stress response and neural activity during psychosocial stress. Using functional magnetic resonance imaging in healthy subjects with and without a history of ELS, we found attenuated hormonal reactivity and significantly reduced limbic deactivation after OXT administration in subjects without a history of ELS. Subjects who experienced ELS showed both blunted stress reactivity and limbic deactivation during stress. Furthermore, in these subjects OXT had opposite effects with increased hormonal reactivity and increased limbic deactivation. Our results might implicate that reduced limbic deactivation and hypothalamic–pituitary–adrenal axis responsivity during psychosocial stress are markers for biological resilience after ELS. Effects of OXT in subjects with a history of maltreatment could therefore be considered detrimental and suggest careful consideration of OXT administration in such individuals. PMID:24478326

  15. Early life stress modulates oxytocin effects on limbic system during acute psychosocial stress.

    PubMed

    Grimm, Simone; Pestke, Karin; Feeser, Melanie; Aust, Sabine; Weigand, Anne; Wang, Jue; Wingenfeld, Katja; Pruessner, Jens C; La Marca, Roberto; Böker, Heinz; Bajbouj, Malek

    2014-11-01

    Early life stress (ELS) is associated with altered stress responsivity, structural and functional brain changes and an increased risk for the development of psychopathological conditions in later life. Due to its behavioral and physiological effects, the neuropeptide oxytocin (OXT) is a useful tool to investigate stress responsivity, even though the neurobiological underpinnings of its effects are still unknown. Here we investigate the effects of OXT on cortisol stress response and neural activity during psychosocial stress. Using functional magnetic resonance imaging in healthy subjects with and without a history of ELS, we found attenuated hormonal reactivity and significantly reduced limbic deactivation after OXT administration in subjects without a history of ELS. Subjects who experienced ELS showed both blunted stress reactivity and limbic deactivation during stress. Furthermore, in these subjects OXT had opposite effects with increased hormonal reactivity and increased limbic deactivation. Our results might implicate that reduced limbic deactivation and hypothalamic-pituitary-adrenal axis responsivity during psychosocial stress are markers for biological resilience after ELS. Effects of OXT in subjects with a history of maltreatment could therefore be considered detrimental and suggest careful consideration of OXT administration in such individuals. PMID:24478326

  16. Neuronal connectivity and interactions between the auditory and limbic systems. Effects of noise and tinnitus.

    PubMed

    Kraus, Kari Suzanne; Canlon, Barbara

    2012-06-01

    Acoustic experience such as sound, noise, or absence of sound induces structural or functional changes in the central auditory system but can also affect limbic regions such as the amygdala and hippocampus. The amygdala is particularly sensitive to sound with valence or meaning, such as vocalizations, crying or music. The amygdala plays a central role in auditory fear conditioning, regulation of the acoustic startle response and can modulate auditory cortex plasticity. A stressful acoustic stimulus, such as noise, causes amygdala-mediated release of stress hormones via the HPA-axis, which may have negative effects on health, as well as on the central nervous system. On the contrary, short-term exposure to stress hormones elicits positive effects such as hearing protection. The hippocampus can affect auditory processing by adding a temporal dimension, as well as being able to mediate novelty detection via theta wave phase-locking. Noise exposure affects hippocampal neurogenesis and LTP in a manner that affects structural plasticity, learning and memory. Tinnitus, typically induced by hearing malfunctions, is associated with emotional stress, depression and anatomical changes of the hippocampus. In turn, the limbic system may play a role in the generation as well as the suppression of tinnitus indicating that the limbic system may be essential for tinnitus treatment. A further understanding of auditory-limbic interactions will contribute to future treatment strategies of tinnitus and noise trauma. PMID:22440225

  17. TRIMETHYLTIN, A SELECTIVE LIMBIC SYSTEM NEUROTOXICANT, IMPAIRS RADIAL-ARM MAZE PERFORMANCE

    EPA Science Inventory

    Rats were trained for fifteen sessions in an automated eight arm radial maze prior to treatment with 6 mg/kg trimethyltin chloride. This compound is a neurotoxicant which primarily damages the limbic system, in particular pyramidal cells in the CA3 region of the hippocampus. Foll...

  18. Morphological deficits in noradrenergic neurons in GEPR-9s stem from abnormalities in both the locus coeruleus and its target tissues.

    PubMed

    Ryu, J R; Jobe, P C; Milbrandt, J C; Mishra, P K; Clough, R W; Browning, R A; Dailey, J W; Seo, D O; Ko, K H

    1999-03-01

    The epileptic condition of the genetically epilepsy-prone rat (GEPR) appears to be caused partially by deficiencies in the locus coeruleus (LC) innervation of the superior colliculus (SC). Previous studies provide quantitative documentation of noradrenergic morphological deficits in the moderately epileptic GEPR-3. The present findings extend these studies by applying cell culture methodology to assessments of the severely epileptic GEPR-9. Our data show that total neurite length, the number of neurite branch points per cell, the cross-sectional area of cell bodies, and the cell perimeter are deficient in noradrenergic neurons in LC + SC cocultures derived exclusively from GEPR-9s compared to analogous cocultures obtained solely from nonepileptic control rats. Partial restoration of LC neuron morphology toward normal occurs when the GEPR-9 SC component of the coculture is replaced with nonepileptic control SC. Finally, when the GEPR-9 SC is cocultured with the control LC, a partial morphological deficit occurs in the otherwise normal noradrenergic neurons. However, the magnitude of this deficit is less than that observed in noradrenergic neurons of the GEPR-9 LC cocultured with the control SC. These data support the hypothesis that the developmental deficiencies of noradrenergic neurons of the GEPR-9 are derived from two sources, the LC and its target tissue, in this case, the SC. Also, intrinsic abnormalities of the LC appear to make a more pronounced contribution to the noradrenergic deficits than do those which reside in the SC. PMID:10192779

  19. Limbic associated pelvic pain: a hypothesis to explain the diagnostic relationships and features of patients with chronic pelvic pain.

    PubMed

    Fenton, Bradford W

    2007-01-01

    Limbic associated pelvic pain is a proposed pathophysiology designed to explain features commonly encountered in patients with chronic pelvic pain, including the presence of multiple pain diagnoses, the frequency of previous abuse, the minimal or discordant pathologic changes of the involved organs, the paradoxical effectiveness of many treatments, and the recurrent nature of the condition. These conditions include endometriosis, interstitial cystitis, irritable bowel syndrome, levator ani syndrome, pelvic floor tension myalgia, vulvar vestibulitis, and vulvodynia. The hypothesis is based on recent improvements in the understanding of pain processing pathways in the central nervous system, and in particular the role of limbic structures, especially the anterior cingulate cortex, hippocampus and amygdala, in chronic and affective pain perception. Limbic associated pelvic pain is hypothesized to occur in patients with chronic pelvic pain out of proportion to any demonstrable pathology (hyperalgesia), and with more than one demonstrable pain generator (allodynia), and who are susceptible to development of the syndrome. This most likely occurs as a result of childhood sexual abuse but may include other painful pelvic events or stressors, which lead to limbic dysfunction. This limbic dysfunction is manifest both as an increased sensitivity to pain afferents from pelvic organs, and as an abnormal efferent innervation of pelvic musculature, both visceral and somatic. The pelvic musculature undergoes tonic contraction as a result of limbic efferent stimulation, which produces the minimal changes found on pathological examination, and generates a further sensation of pain. The pain afferents from these pelvic organs then follow the medial pain pathway back to the sensitized, hypervigilant limbic system. Chronic stimulation of the limbic system by pelvic pain afferents again produces an efferent contraction of the pelvic muscles, thus perpetuating the cycle. This cycle is

  20. Terminal field specificity of forebrain efferent axons to the pontine parabrachial nucleus and medullary reticular formation

    PubMed Central

    Zhang, Chi; Kang, Yi; Lundy, Robert F.

    2010-01-01

    The pontine parabrachial nucleus (PBN) and medullary reticular formation (RF) are hindbrain regions that, respectively, process sensory input and coordinate motor output related to ingestive behavior. Neural processing in each hindbrain site is subject to modulation originating from several forebrain structures including the insular gustatory cortex (IC), bed nucleus of the stria terminalis (BNST), central nucleus of the amygdala (CeA), and lateral hypothalamus (LH). The present study combined electrophysiology and retrograde tracing techniques to determine the extent of overlap between neurons within the IC, BNST, CeA and LH that target both the PBN and RF. One fluorescent retrograde tracer, red (RFB) or green (GFB) latex microbeads, was injected into the gustatory PBN under electrophysiological guidance and a different retrograde tracer, GFB or fluorogold (FG), into the ipsilateral RF using the location of gustatory NST as a point of reference. Brain tissue containing each forebrain region was sectioned, scanned using a confocal microscope, and scored for the number of single and double labeled neurons. Neurons innervating the RF only, the PBN only, or both the medullary RF and PBN were observed, largely intermingled, in each forebrain region. The CeA contained the largest number of cells retrogradely labeled after tracer injection into either hindbrain region. For each forebrain area except the IC, the origin of descending input to the RF and PBN was almost entirely ipsilateral. Axons from a small percentage of hindbrain projecting forebrain neurons targeted both the PBN and RF. Target specific and non specific inputs from a variety of forebrain nuclei to the hindbrain likely reflect functional specialization in the control of ingestive behaviors. PMID:21040715

  1. Effects of hypocretin (orexin) neuronal loss on sleep and extracellular adenosine levels in the basal forebrain

    PubMed Central

    Murillo-Rodriguez, Eric; Liu, Meng; Blanco-Centurion, Carlos; Shiromani, Priyattam J.

    2009-01-01

    Neurons containing the neuropeptide hypocretin (orexin) are localized only in the lateral hypothalamus from where they innervate multiple regions implicated in arousal, including the basal forebrain. HCRT activation of downstream arousal neurons is likely to stimulate release of endogenous factors. One such factor is adenosine (AD), which in the basal forebrain increases with waking and decreases with sleep, and is hypothesized to regulate the waxing and waning of sleep drive. Does loss of HCRT neurons affect AD levels in the basal forebrain? Is the increased sleep that accompanies HCRT loss a consequence of higher AD levels in the basal forebrain? In the present study, we investigate these questions by lesioning the HCRT neurons (hypocretin-2-saporin) and measuring sleep and extracellular levels of AD in the basal forebrain. In separate groups of rats, the neurotoxin HCRT2-SAP or saline were administered locally to the lateral hypothalamus and 80 days later AD and sleep were assessed. Rats given the neurotoxin had a 94% loss of the HCRT neurons. These rats awake less at night, and had more REM sleep, which is consistent with a HCRT hypofunction. These rats also had more sleep after brief periods of sleep deprivation. However, in the lesioned rats, AD levels did not increase with 6h sleep deprivation, whereas such an increase in AD occurred in rats without lesion of the HCRT neurons. These findings indicate that AD levels do not increase with waking in rats with a HCRT lesion, and that the increased sleep in these rats occurs independently of AD levels in the basal forebrain. PMID:18783368

  2. Candidate gene associations with mood disorder, cognitive vulnerability, and fronto-limbic volumes

    PubMed Central

    Frazier, Thomas W; Youngstrom, Eric A; Frankel, Brian A; Zunta-Soares, Giovana B; Sanches, Marsal; Escamilla, Michael; Nielsen, David A; Soares, Jair C

    2014-01-01

    Background Four of the most consistently replicated variants associated with mood disorder occur in genes important for synaptic function: ANK3 (rs10994336), BDNF (rs6265), CACNA1C (rs1006737), and DGKH (rs1170191). Aims The present study examined associations between these candidates, mood disorder diagnoses, cognition, and fronto-limbic regions implicated in affect regulation. Methods and materials Participants included 128 individuals with bipolar disorder (33% male, Mean age = 38.5), 48 with major depressive disorder (29% male, Mean age = 40.4), and 149 healthy controls (35% male, Mean age = 36.5). Genotypes were determined by 5′-fluorogenic exonuclease assays (TaqMan®). Fronto-limbic volumes were obtained from high resolution brain images using Freesurfer. Chi-square analyses, bivariate correlations, and mediational models examined relationships between genetic variants, mood diagnoses, cognitive measures, and brain volumes. Results Carriers of the minor BDNF and ANK3 alleles showed nonsignificant trends toward protective association in controls relative to mood disorder patients (P = 0.047). CACNA1C minor allele carriers had larger bilateral caudate, insula, globus pallidus, frontal pole, and nucleus accumbens volumes (smallest r = 0.13, P = 0.043), and increased IQ (r = 0.18, P < 0.001). CACNA1C associations with brain volumes and IQ were independent; larger fronto-limbic volumes did not mediate increased IQ. Other candidate variants were not significantly associated with diagnoses, cognition, or fronto-limbic volumes. Discussion and conclusions CACNA1C may be associated with biological systems altered in mood disorder. Increases in fronto-limbic volumes and cognitive ability associated with CACNA1C minor allele genotypes are congruent with findings in healthy samples and may be a marker for increased risk for neuropsychiatric phenotypes. Even larger multimodal studies are needed to quantify the magnitude and specificity of genetic

  3. Locus coeruleus noradrenergic innervation of the amygdala facilitates alerting-induced constriction of the rat tail artery.

    PubMed

    Mohammed, Mazher; Kulasekara, Keerthi; Ootsuka, Youichirou; Blessing, William W

    2016-06-01

    The amygdala, innervated by the noradrenergic locus coeruleus, processes salient environmental events. α2-adrenoceptor-stimulating drugs (clonidine-like agents) suppress the behavioral and physiological components of the response to salient events. Activation of sympathetic outflow to the cutaneous vascular bed is part of the physiological response to salience-mediated activation of the amygdala. We have determined whether acute systemic and intra-amygdala administration of clonidine, and chronic immunotoxin-mediated destruction of the noradrenergic innervation of the amygdala, impairs salience-related vasoconstrictor episodes in the tail artery of conscious freely moving Sprague-Dawley rats. After acute intraperitoneal injection of clonidine (10, 50, and 100 μg/kg), there was a dose-related decrease in the reduction in tail blood flow elicited by alerting stimuli, an effect prevented by prior administration of the α2-adrenergic blocking drug idazoxan (1 mg/kg ip or 75 nmol bilateral intra-amygdala). A dose-related decrease in alerting-induced tail artery vasoconstriction was also observed after bilateral intra-amygdala injection of clonidine (5, 10, and 20 nmol in 200 nl), an effect substantially prevented by prior bilateral intra-amygdala injection of idazoxan. Intra-amygdala injection of idazoxan by itself did not alter tail artery vasoconstriction elicited by alerting stimuli. Intra-amygdala injection of saporin coupled to antibodies to dopamine-β-hydroxylase (immunotoxin) destroyed the noradrenergic innervation of the amygdala and the parent noradrenergic neurons in the locus coeruleus. The reduction in tail blood flow elicited by standardized alerting stimuli was substantially reduced in immunotoxin-treated rats. Thus, inhibiting the release of noradrenaline within the amygdala reduces activation of the sympathetic outflow to the vascular beds elicited by salient events. PMID:27101292

  4. DSP4, a selective neurotoxin for the locus coeruleus noradrenergic system. A review of its mode of action.

    PubMed

    Ross, Svante B; Stenfors, Carina

    2015-01-01

    DSP4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride) is a selective neurotoxin for the locus coeruleus noradrenergic system in the rodent and bird brain. It readily passes the blood-brain barrier and cyclizes to a reactive aziridinium derivative that is accumulated into the noradrenergic nerve terminals via the noradrenaline transporter. DSP4 is also an irreversible inhibitor of this transporter. Within the nerve terminals the aziridinium derivative reacts with unknown vital cellular components, destroying the terminals. At the dose 50 mg/kg i.p. this is characterized by a rapid and long-lasting loss of noradrenaline and a slower decrease in the dopamine-β-hydroxylase enzyme activity and immunoreactivity in the regions innervated from locus coeruleus. The tissue level of noradrenaline is reduced to 10-30% of the normal value. The extraneuronal concentration is, on the other hand, increased due to inflow from non-lesioned regions. Like the peripheral sympathetic nerves the non-locus coeruleus noradrenergic systems in the rodent brain is resistant to the neurotoxic action of DSP4. Serotoninergic and dopaminergic nerves are only slightly or not at all affected by DSP4. The neurotoxic effect is counteracted by pretreatment with noradrenaline uptake inhibitors (e.g., desipramine). MAO-B inhibitors of the N-propargylamine type (e.g., selegiline) also counteract the DSP4-induced neurotoxicity with another, yet unknown mechanism. Because of its selectivity for the locus coeruleus system DSP4 is a useful tool in studies of the functional role of this noradrenergic system in the brain. PMID:24964753

  5. An exploratory association study of the influence of noradrenergic genes and childhood trauma in Borderline Personality Disorder.

    PubMed

    Martín-Blanco, Ana; Ferrer, Marc; Soler, Joaquim; Arranz, Maria Jesús; Vega, Daniel; Bauzà, Joana; Calvo, Natalia; Elices, Matilde; Sanchez-Mora, Cristina; García-Martinez, Iris; Salazar, Juliana; Ribases, Marta; Carmona, Cristina; Prat, Mónica; Pascual, Juan C

    2015-09-30

    This study investigated the possible association of 40 polymorphisms within 4 noradrenergic genes with BPD risk and the modulating effect of childhood trauma on these associations in 481 BPD subjects and 442 controls. COMT rs5993882, DBH rs77905 and SLC6A2 rs1814270 showed associations with BPD, which were modulated by childhood trauma. However, none of these findings survived Bonferroni correction. Further investigation is needed to clarify the involvement of these genes in BPD pathogenesis. PMID:26216165

  6. Enhanced noradrenergic activity in the amygdala contributes to hyperarousal in an animal model of PTSD.

    PubMed

    Ronzoni, Giacomo; Del Arco, Alberto; Mora, Francisco; Segovia, Gregorio

    2016-08-01

    Increased activity of the noradrenergic system in the amygdala has been suggested to contribute to the hyperarousal symptoms associated with post-traumatic stress disorder (PTSD). However, only two studies have examined the content of noradrenaline or its metabolites in the amygdala of rats previously exposed to traumatic stress showing inconsistent results. The aim of this study was to investigate the effects of an inescapable foot shock (IFS) procedure (1) on reactivity to novelty in an open-field (as an index of hyperarousal), and (2) on noradrenaline release in the amygdala during an acute stress. To test the role of noradrenaline in amygdala, we also investigated the effects of microinjections of propranolol, a β-adrenoreceptor antagonist, and clenbuterol, a β-adrenoreceptor agonist, into the amygdala of IFS and control animals. Finally, we evaluated the expression of mRNA levels of β-adrenoreceptors (β1 and β2) in the amygdala, the hippocampus and the prefrontal cortex. Male Wistar rats (3 months) were stereotaxically implanted with bilateral guide cannulae. After recovering from surgery, animals were exposed to IFS (10 shocks, 0.86mA, and 6s per shock) and seven days later either microdialysis or microinjections were performed in amygdala. Animals exposed to IFS showed a reduced locomotion compared to non-shocked animals during the first 5min in the open-field. In the amygdala, IFS animals showed an enhanced increase of noradrenaline induced by stress compared to control animals. Bilateral microinjections of propranolol (0.5μg) into the amygdala one hour before testing in the open-field normalized the decreased locomotion observed in IFS animals. On the other hand, bilateral microinjections of clenbuterol (30ng) into the amygdala of control animals did not change the exploratory activity induced by novelty in the open field. IFS modified the mRNA expression of β1 and β2 adrenoreceptors in the prefrontal cortex and the hippocampus. These results

  7. Locomotor-activated neurons of the cat. II. Noradrenergic innervation and colocalization with NEα1a or NEα2b receptors in the thoraco-lumbar spinal cord

    PubMed Central

    Johnson, Dawn M. G.; Riesgo, Mirta I.; Pinzon, Alberto

    2011-01-01

    Norepinephrine (NE) is a strong modulator and/or activator of spinal locomotor networks. Thus noradrenergic fibers likely contact neurons involved in generating locomotion. The aim of the present study was to investigate the noradrenergic innervation of functionally related, locomotor-activated neurons within the thoraco-lumbar spinal cord. This was accomplished by immunohistochemical colocalization of noradrenergic fibers using dopamine-β-hydroxylase or NEα1A and NEα2B receptors with cells expressing the c-fos gene activity-dependent marker Fos. Experiments were performed on paralyzed, precollicular-postmamillary decerebrate cats, in which locomotion was induced by electrical stimulation of the mesencephalic locomotor region. The majority of Fos labeled neurons, especially abundant in laminae VII and VIII throughout the thoraco-lumbar (T13-L7) region of locomotor animals, showed close contacts with multiple noradrenergic boutons. A small percentage (10–40%) of Fos neurons in the T7-L7 segments showed colocalization with NEα1A receptors. In contrast, NEα2B receptor immunoreactivity was observed in 70–90% of Fos cells, with no obvious rostrocaudal gradient. In comparison with results obtained from our previous study on the same animals, a significantly smaller proportion of Fos labeled neurons were innervated by noradrenergic than serotonergic fibers, with significant differences observed for laminae VII and VIII in some segments. In lamina VII of the lumbar segments, the degree of monoaminergic receptor subtype/Fos colocalization examined statistically generally fell into the following order: NEα2B = 5-HT2A ≥ 5-HT7 = 5-HT1A > NEα1A. These results suggest that noradrenergic modulation of locomotion involves NEα1A/NEα2B receptors on noradrenergic-innervated locomotor-activated neurons within laminae VII and VIII of thoraco-lumbar segments. Further study of the functional role of these receptors in locomotion is warranted. PMID:21307324

  8. Statins Promote Long-Term Recovery after Ischemic Stroke by Reconnecting Noradrenergic Neuronal Circuitry

    PubMed Central

    Cho, Kyoung Joo; Cheon, So Young; Kim, Gyung Whan

    2015-01-01

    Inhibitors of HMG-CoA reductase (statins), widely used to lower cholesterol in coronary heart and vascular disease, are effective drugs in reducing the risk of stroke and improving its outcome in the long term. After ischemic stroke, cardiac autonomic dysfunction and psychological problems are common complications related to deficits in the noradrenergic (NA) system. This study investigated the effects of statins on the recovery of NA neuron circuitry and its function after transient focal cerebral ischemia (tFCI). Using the wheat germ agglutinin (WGA) transgene technique combined with the recombinant adenoviral vector system, NA-specific neuronal pathways were labeled, and were identified in the locus coeruleus (LC), where NA neurons originate. NA circuitry in the atorvastatin-treated group recovered faster than in the vehicle-treated group. The damaged NA circuitry was partly reorganized with the gradual recovery of autonomic dysfunction and neurobehavioral deficit. Newly proliferated cells might contribute to reorganizing NA neurons and lead anatomic and functional recovery of NA neurons. Statins may be implicated to play facilitating roles in the recovery of the NA neuron and its function. PMID:26448880

  9. Transdermal neuromodulation of noradrenergic activity suppresses psychophysiological and biochemical stress responses in humans.

    PubMed

    Tyler, William J; Boasso, Alyssa M; Mortimore, Hailey M; Silva, Rhonda S; Charlesworth, Jonathan D; Marlin, Michelle A; Aebersold, Kirsten; Aven, Linh; Wetmore, Daniel Z; Pal, Sumon K

    2015-01-01

    We engineered a transdermal neuromodulation approach that targets peripheral (cranial and spinal) nerves and utilizes their afferent pathways as signaling conduits to influence brain function. We investigated the effects of this transdermal electrical neurosignaling (TEN) method on sympathetic physiology under different experimental conditions. The TEN method involved delivering high-frequency pulsed electrical currents to ophthalmic and maxillary divisions of the right trigeminal nerve and cervical spinal nerve afferents. Under resting conditions, TEN significantly suppressed basal sympathetic tone compared to sham as indicated by functional infrared thermography of facial temperatures. In a different experiment, subjects treated with TEN reported significantly lower levels of tension and anxiety on the Profile of Mood States scale compared to sham. In a third experiment when subjects were experimentally stressed TEN produced a significant suppression of heart rate variability, galvanic skin conductance, and salivary α-amylase levels compared to sham. Collectively these observations demonstrate TEN can dampen basal sympathetic tone and attenuate sympathetic activity in response to acute stress induction. Our physiological and biochemical observations are consistent with the hypothesis that TEN modulates noradrenergic signaling to suppress sympathetic activity. We conclude that dampening sympathetic activity in such a manner represents a promising approach to managing daily stress. PMID:26353920

  10. Transdermal neuromodulation of noradrenergic activity suppresses psychophysiological and biochemical stress responses in humans

    PubMed Central

    Tyler, William J.; Boasso, Alyssa M.; Mortimore, Hailey M.; Silva, Rhonda S.; Charlesworth, Jonathan D.; Marlin, Michelle A.; Aebersold, Kirsten; Aven, Linh; Wetmore, Daniel Z.; Pal, Sumon K.

    2015-01-01

    We engineered a transdermal neuromodulation approach that targets peripheral (cranial and spinal) nerves and utilizes their afferent pathways as signaling conduits to influence brain function. We investigated the effects of this transdermal electrical neurosignaling (TEN) method on sympathetic physiology under different experimental conditions. The TEN method involved delivering high-frequency pulsed electrical currents to ophthalmic and maxillary divisions of the right trigeminal nerve and cervical spinal nerve afferents. Under resting conditions, TEN significantly suppressed basal sympathetic tone compared to sham as indicated by functional infrared thermography of facial temperatures. In a different experiment, subjects treated with TEN reported significantly lower levels of tension and anxiety on the Profile of Mood States scale compared to sham. In a third experiment when subjects were experimentally stressed TEN produced a significant suppression of heart rate variability, galvanic skin conductance, and salivary α-amylase levels compared to sham. Collectively these observations demonstrate TEN can dampen basal sympathetic tone and attenuate sympathetic activity in response to acute stress induction. Our physiological and biochemical observations are consistent with the hypothesis that TEN modulates noradrenergic signaling to suppress sympathetic activity. We conclude that dampening sympathetic activity in such a manner represents a promising approach to managing daily stress. PMID:26353920

  11. Memory impairment induced by combined disturbance of noradrenergic and dopaminergic neurotransmissions: effects of nootropic drugs.

    PubMed

    Lazarova-Bakarova, M B; Petkova, B P; Todorov, I K; Petkov, V D

    1991-01-01

    The effect of the combined application of the alpha 2-adrenoreceptor agonist clonidine and of the dopaminergic blocker haloperidol on the memory processes was tested on albino rats. The changes in the memory were studied using the following methods: two-way active avoidance with negative reinforcement (shuttle-box) and passive avoidance (step-through). Both clonidine (0.05 mg/kg) and haloperidol (0.5 mg/kg), injected intraperitoneally immediately after the end of the training session, slightly impaired retention in the memory tests used with both training methods. Their combined application, however, caused a marked amnesia. This amnesia model was used to study the effects of the nootropic drugs: adafenoxate and the newly-synthesized compound benzoyl-1, 4-dipyrolydinone (p-P). Administered orally in a dose of 100 mg/kg for 5 days prior to the training session, both adafenoxate and p-P fully eliminate the amnesia caused by the combined application of clonidine and haloperidol. The paper discusses the role of the noradrenergic and dopaminergic neurotransmitter systems for the amnestic effect of the clonidine + haloperidol combination, as well as for the favourable effect on the cognitive functions of the tested nootropic drugs adafenoxate and p-p. PMID:1667717

  12. EVIDENCE FOR A REGIONAL SPECIFICITY IN THE DENSITY AND DISTRIBUTION OF NORADRENERGIC VARICOSITIES IN RAT CORTEX

    PubMed Central

    Agster, Kara L.; Mejias-Aponte, Carlos A.; Clark, Brian D.; Waterhouse, Barry D.

    2012-01-01

    The brainstem nucleus locus coeruleus (LC) is the sole source of norepinephrine (NE)-containing fibers in the mammalian cortex. Previous studies suggest that the density of noradrenergic fibers in rat is relatively uniform across cortical regions and that cells in the nucleus discharge en masse. This implies that activation of the LC results in equivalent release of NE throughout the cortex. However, it is possible that there could be differences in the density of axonal varicosities across regions, and that these differences, rather than a difference in fiber density may contribute to the regulation of NE efflux. Quantification of dopamine beta hydroxylase (DβH) immunostained varicosities was performed on several cortical regions and in the ventral posterior medial (VPM) thalamus using unbiased sampling methods. The density of DβH varicosites is greater in the prefrontal cortex than in motor, somatosensory, or piriform cortices, greater in superficial than in deep layers of cortex, and greater in VPM than in somatosensory cortex. Our results provide anatomical evidence for non-uniform release of NE across functionally discrete cortical regions. This morphology may account for differential, region specific, impact of LC output on different cortical areas. PMID:23184811

  13. Extensive Lesions of Cholinergic Basal Forebrain Neurons Do Not Impair Spatial Working Memory

    ERIC Educational Resources Information Center

    Vuckovich, Joseph A.; Semel, Mara E.; Baxter, Mark G.

    2004-01-01

    A recent study suggests that lesions to all major areas of the cholinergic basal forebrain in the rat (medial septum, horizontal limb of the diagonal band of Broca, and nucleus basalis magnocellularis) impair a spatial working memory task. However, this experiment used a surgical technique that may have damaged cerebellar Purkinje cells. The…

  14. GABAergic Terminals Are a Source of Galanin to Modulate Cholinergic Neuron Development in the Neonatal Forebrain

    PubMed Central

    Keimpema, Erik; Zheng, Kang; Barde, Swapnali Shantaram; Berghuis, Paul; Dobszay, Márton B.; Schnell, Robert; Mulder, Jan; Luiten, Paul G. M.; Xu, Zhiqing David; Runesson, Johan; Langel, Ülo; Lu, Bai; Hökfelt, Tomas; Harkany, Tibor

    2014-01-01

    The distribution and (patho-)physiological role of neuropeptides in the adult and aging brain have been extensively studied. Galanin is an inhibitory neuropeptide that can coexist with γ-aminobutyric acid (GABA) in the adult forebrain. However, galanin's expression sites, mode of signaling, impact on neuronal morphology, and colocalization with amino acid neurotransmitters during brain development are less well understood. Here, we show that galaninergic innervation of cholinergic projection neurons, which preferentially express galanin receptor 2 (GalR2) in the neonatal mouse basal forebrain, develops by birth. Nerve growth factor (NGF), known to modulate cholinergic morphogenesis, increases GalR2 expression. GalR2 antagonism (M871) in neonates reduces the in vivo expression and axonal targeting of the vesicular acetylcholine transporter (VAChT), indispensable for cholinergic neurotransmission. During cholinergic neuritogenesis in vitro, GalR2 can recruit Rho-family GTPases to induce the extension of a VAChT-containing primary neurite, the prospective axon. In doing so, GalR2 signaling dose-dependently modulates directional filopodial growth and antagonizes NGF-induced growth cone differentiation. Galanin accumulates in GABA-containing nerve terminals in the neonatal basal forebrain, suggesting its contribution to activity-driven cholinergic development during the perinatal period. Overall, our data define the cellular specificity and molecular complexity of galanin action in the developing basal forebrain. PMID:23897649

  15. Basal forebrain moderates the magnitude of task-dependent amygdala functional connectivity

    PubMed Central

    Knodt, Annchen R.; Hariri, Ahmad R.

    2015-01-01

    Animal studies reveal that the amygdala promotes attention and emotional memory, in part, by driving activity in downstream target regions including the prefrontal cortex (PFC) and hippocampus. Prior work has demonstrated that the amygdala influences these regions directly through monosynaptic glutamatergic signaling, and indirectly by driving activity of the cholinergic basal forebrain and subsequent downstream acetylcholine release. Yet to date, no work has addressed the functional relevance of the cholinergic basal forebrain in facilitating signaling from the amygdala in humans. We set out to determine how blood oxygen level-dependent signal within the amygdala and cholinergic basal forebrain interact to predict neural responses within downstream targets. Here, we use functional connectivity analyses to demonstrate that the cholinergic basal forebrain moderates increased amygdala connectivity with both the PFC and the hippocampus during the processing of biologically salient stimuli in humans. We further demonstrate that functional variation within the choline transporter gene predicts the magnitude of this modulatory effect. Collectively, our results provide novel evidence for the importance of cholinergic signaling in modulating neural pathways supporting arousal, attention and memory in humans. Further, our results may shed light on prior association studies linking functional variation within the choline transporter gene and diagnoses of major depression and attention-deficit hyperactivity disorder. PMID:24847112

  16. Serotonin 5-HT4 receptors and forebrain cholinergic system: receptor expression in identified cell populations.

    PubMed

    Peñas-Cazorla, Raúl; Vilaró, M Teresa

    2015-11-01

    Activation of serotonin 5-HT4 receptors has pro-cognitive effects on memory performance. The proposed underlying neurochemical mechanism is the enhancement of acetylcholine release in frontal cortex and hippocampus elicited by 5-HT4 agonists. Although 5-HT4 receptors are present in brain areas related to cognition, e.g., hippocampus and cortex, the cellular localization of the receptors that might modulate acetylcholine release is unknown at present. We have analyzed, using dual label in situ hybridization, the cellular localization of 5-HT4 receptor mRNA in identified neuronal populations of the rat basal forebrain, which is the source of the cholinergic innervation to cortex and hippocampus. 5-HT4 receptor mRNA was visualized with isotopically labeled oligonucleotide probes, whereas cholinergic, glutamatergic, GABAergic and parvalbumin-synthesizing neurons were identified with digoxigenin-labeled oligonucleotide probes. 5-HT4 receptor mRNA was not detected in the basal forebrain cholinergic cell population. In contrast, basal forebrain GABAergic, parvalbumin synthesizing, and glutamatergic cells contained 5-HT4 receptor mRNA. Hippocampal and cortical glutamatergic neurons also express this receptor. These results indicate that 5-HT4 receptors are not synthesized by cholinergic cells, and thus would be absent from cholinergic terminals. In contrast, several non-cholinergic cell populations within the basal forebrain and its target hippocampal and cortical areas express these receptors and are thus likely to mediate the enhancement of acetylcholine release elicited by 5-HT4 agonists. PMID:25183542

  17. Relative and absolute quantification of postsynaptic density proteome isolated from rat forebrain and cerebellum.

    PubMed

    Cheng, Dongmei; Hoogenraad, Casper C; Rush, John; Ramm, Elizabeth; Schlager, Max A; Duong, Duc M; Xu, Ping; Wijayawardana, Sameera R; Hanfelt, John; Nakagawa, Terunaga; Sheng, Morgan; Peng, Junmin

    2006-06-01

    The postsynaptic density (PSD) of central excitatory synapses is essential for postsynaptic signaling, and its components are heterogeneous among different neuronal subtypes and brain structures. Here we report large scale relative and absolute quantification of proteins in PSDs purified from adult rat forebrain and cerebellum. PSD protein profiles were determined using the cleavable ICAT strategy and LC-MS/MS. A total of 296 proteins were identified and quantified with 43 proteins exhibiting statistically significant abundance change between forebrain and cerebellum, indicating marked molecular heterogeneity of PSDs between different brain regions. Moreover we utilized absolute quantification strategy, in which synthetic isotope-labeled peptides were used as internal standards, to measure the molar abundance of 32 key PSD proteins in forebrain and cerebellum. These data confirm the abundance of calcium/calmodulin-dependent protein kinase II and PSD-95 and reveal unexpected stoichiometric ratios between glutamate receptors, scaffold proteins, and signaling molecules in the PSD. Our data also demonstrate that the absolute quantification method is well suited for targeted quantitative proteomic analysis. Overall this study delineates a crucial molecular difference between forebrain and cerebellar PSDs and provides a quantitative framework for measuring the molecular stoichiometry of the PSD. PMID:16507876

  18. Conserved Noncoding Sequences Regulate lhx5 Expression in the Zebrafish Forebrain

    PubMed Central

    Sun, Liu; Chen, Fengjiao; Peng, Gang

    2015-01-01

    The LIM homeobox family protein Lhx5 plays important roles in forebrain development in the vertebrates. The lhx5 gene exhibits complex temporal and spatial expression patterns during early development but its transcriptional regulation mechanisms are not well understood. Here, we have used transgenesis in zebrafish in order to define regulatory elements that drive lhx5 expression in the forebrain. Through comparative genomic analysis we identified 10 non-coding sequences conserved in five teleost species. We next examined the enhancer activities of these conserved non-coding sequences with Tol2 transposon mediated transgenesis. We found a proximately located enhancer gave rise to robust reporter EGFP expression in the forebrain regions. In addition, we identified an enhancer located at approximately 50 kb upstream of lhx5 coding region that is responsible for reporter gene expression in the hypothalamus. We also identify an enhancer located approximately 40 kb upstream of the lhx5 coding region that is required for expression in the prethalamus (ventral thalamus). Together our results suggest discrete enhancer elements control lhx5 expression in different regions of the forebrain. PMID:26147098

  19. [Method of Calculating the Distance Between the Classes of the Structural Components of the Forebrain Birds].

    PubMed

    Voronov, L N; Konstantinov, V Y

    2016-01-01

    The method of calculating the distance between the classes of the structural components of the brain of birds. Compared interclass distances of glia, neurons and neuroglial complexes in the forebrain hooded crow (Corvus cornix) (a bird with a highly rational activity) and common crossbill (Loxia curvirostra) (birds with a medium level of rational activity). PMID:27263281

  20. Pain sensitivity following loss of cholinergic basal forebrain (CBF) neurons in the rat.

    PubMed

    Vierck, C J; Yezierski, R P; Wiley, R G

    2016-04-01

    Flexion/withdrawal reflexes are attenuated by spinal, intracerebroventricular (ICV) and systemic delivery of cholinergic agonists. In contrast, some affective reactions to pain are suppressed by systemic cholinergic antagonism. Attention to aversive stimulation can be impaired, as is classical conditioning of fear and anxiety to aversive stimuli and psychological activation of stress reactions that exacerbate pain. Thus, in contrast to the suppressive effects of cholinergic agonism on reflexes, pain sensitivity and affective reactions to pain could be attenuated by reduced cerebral cholinergic activation. This possibility was evaluated in the present study, using an operant test of escape from nociceptive thermal stimulation (10 °C and 44.5 °C) before and after destruction of basal forebrain cholinergic neurons. ICV injection of 192 IgG-saporin produced widespread loss of basal forebrain cholinergic innervation of the cerebral cortex and hippocampus. Post-injection, escape from thermal stimulation was decreased with no indication of recovery for upto 19 weeks. Also, the normal hyperalgesic effect of sound stress was absent after ICV 192-sap. Effects of cerebral cholinergic denervation or stress on nociceptive licking and guarding reflexes were not consistent with the effects on operant escape, highlighting the importance of evaluating pain sensitivity of laboratory animals with an operant behavioral test. These results reveal that basal forebrain cholinergic transmission participates in the cerebral processing of pain, which may be relevant to the pain sensitivity of patients with Alzheimer's disease who have prominent degeneration of basal forebrain cholinergic neurons. PMID:26812034

  1. Probucol attenuates oxidative stress, energy starvation, and nitric acid production following transient forebrain ischemia in the rat hippocampus.

    PubMed

    Al-Majed, Abdulhakeem A

    2011-01-01

    Oxidative stress and energy depletion are believed to participate in hippocampal neuronal damage after forebrain ischemia. This study has been initiated to investigate the potential neuroprotective effects of probucol, a lipid-lowering drug with strong antioxidant properties, against transient forebrain ischemia-induced neuronal damage and biochemical abnormalities in rat hippocampal CA1 region. Adult male Wistar albino rats were subjected to forebrain ischemia and injected with probucol for the next 7 successive days, and compared to controls. Forebrain ischemia resulted in a significant decrease in the number of intact neurons (77%), glutathione (GSH), and adenosine triphosphate (ATP), and a significant increase in thiobarbituric acid reactive substances (TBARS) and total nitrate/nitrite, (NO(x)) production in hippocampal tissues. The administration of probucol attenuated forebrain ischemia-induced neuronal damage, manifested as a complete reversal of the decrease in the number of intact neurons, ATP and GSH and the increase in TBARS and NO(x) in hippocampal tissues. This study demonstrates that probucol treatment abates forebrain ischemia-induced hippocampal neuronal loss, energy depletion, and oxidative stress in hippocampal CA1 region. Thus, probucol could be a promising neuroprotective agent in the treatment of forebrain ischemia. PMID:21904644

  2. Optogenetic Dissection of the Basal Forebrain Neuromodulatory Control of Cortical Activation, Plasticity, and Cognition

    PubMed Central

    Brown, Ritchie E.; Hussain Shuler, Marshall G.; Petersen, Carl C.H.; Kepecs, Adam

    2015-01-01

    The basal forebrain (BF) houses major ascending projections to the entire neocortex that have long been implicated in arousal, learning, and attention. The disruption of the BF has been linked with major neurological disorders, such as coma and Alzheimer's disease, as well as in normal cognitive aging. Although it is best known for its cholinergic neurons, the BF is in fact an anatomically and neurochemically complex structure. Recent studies using transgenic mouse lines to target specific BF cell types have led to a renaissance in the study of the BF and are beginning to yield new insights about cell-type-specific circuit mechanisms during behavior. These approaches enable us to determine the behavioral conditions under which cholinergic and noncholinergic BF neurons are activated and how they control cortical processing to influence behavior. Here we discuss recent advances that have expanded our knowledge about this poorly understood brain region and laid the foundation for future cell-type-specific manipulations to modulate arousal, attention, and cortical plasticity in neurological disorders. SIGNIFICANCE STATEMENT Although the basal forebrain is best known for, and often equated with, acetylcholine-containing neurons that provide most of the cholinergic innervation of the neocortex, it is in fact an anatomically and neurochemically complex structure. Recent studies using transgenic mouse lines to target specific cell types in the basal forebrain have led to a renaissance in this field and are beginning to dissect circuit mechanisms in the basal forebrain during behavior. This review discusses recent advances in the roles of basal forebrain cholinergic and noncholinergic neurons in cognition via their dynamic modulation of cortical activity. PMID:26468190

  3. Dopamine receptor activation modulates GABA neuron migration from the basal forebrain to the cerebral cortex.

    PubMed

    Crandall, James E; McCarthy, Deirdre M; Araki, Kiyomi Y; Sims, John R; Ren, Jia-Qian; Bhide, Pradeep G

    2007-04-01

    GABA neurons of the cerebral cortex and other telencephalic structures are produced in the basal forebrain and migrate to their final destinations during the embryonic period. The embryonic basal forebrain is enriched in dopamine and its receptors, creating a favorable environment for dopamine to influence GABA neuron migration. However, whether dopamine receptor activation can influence GABA neuron migration is not known. We show that dopamine D1 receptor activation promotes and D2 receptor activation decreases GABA neuron migration from the medial and caudal ganglionic eminences to the cerebral cortex in slice preparations of embryonic mouse forebrain. Slice preparations from D1 or D2 receptor knock-out mouse embryos confirm the findings. In addition, D1 receptor electroporation into cells of the basal forebrain and pharmacological activation of the receptor promote migration of the electroporated cells to the cerebral cortex. Analysis of GABA neuron numbers in the cerebral wall of the dopamine receptor knock-out mouse embryos further confirmed the effects of dopamine receptor activation on GABA neuron migration. Finally, dopamine receptor activation mobilizes striatal neuronal cytoskeleton in a manner consistent with the effects on neuronal migration. These data show that impairing the physiological balance between D1 and D2 receptors can alter GABA neuron migration from the basal forebrain to the cerebral cortex. The intimate relationship between dopamine and GABA neuron development revealed here may offer novel insights into developmental disorders such as schizophrenia, attention deficit or autism, and fetal cocaine exposure, all of which are associated with dopamine and GABA imbalance. PMID:17409246

  4. Diurnal cortisol amplitude and fronto-limbic activity in response to stressful stimuli.

    PubMed

    Cunningham-Bussel, Amy C; Root, James C; Butler, Tracy; Tuescher, Oliver; Pan, Hong; Epstein, Jane; Weisholtz, Daniel S; Pavony, Michelle; Silverman, Michael E; Goldstein, Martin S; Altemus, Margaret; Cloitre, Marylene; Ledoux, Joseph; McEwen, Bruce; Stern, Emily; Silbersweig, David

    2009-06-01

    The development and exacerbation of many psychiatric and neurologic conditions are associated with dysregulation of the hypothalamic pituitary adrenal (HPA) axis as measured by aberrant levels of cortisol secretion. Here we report on the relationship between the amplitude of diurnal cortisol secretion, measured across 3 typical days in 18 healthy individuals, and blood oxygen level dependant (BOLD) response in limbic fear/stress circuits, elicited by in-scanner presentation of emotionally negative stimuli, specifically, images of the World Trade Center (WTC) attack. Results indicate that subjects who secrete a greater amplitude of cortisol diurnally demonstrate less brain activation in limbic regions, including the amygdala and hippocampus/parahippocampus, and hypothalamus during exposure to traumatic WTC-related images. Such initial findings can begin to link our understanding, in humans, of the relationship between the diurnal amplitude of a hormone integral to the stress response, and those neuroanatomical regions that are implicated as both modulating and being modulated by that response. PMID:19135805

  5. A Primary Role for Nucleus Accumbens and Related Limbic Network in Vocal Tics.

    PubMed

    McCairn, Kevin W; Nagai, Yuji; Hori, Yukiko; Ninomiya, Taihei; Kikuchi, Erika; Lee, Ju-Young; Suhara, Tetsuya; Iriki, Atsushi; Minamimoto, Takafumi; Takada, Masahiko; Isoda, Masaki; Matsumoto, Masayuki

    2016-01-20

    Inappropriate vocal expressions, e.g., vocal tics in Tourette syndrome, severely impact quality of life. Neural mechanisms underlying vocal tics remain unexplored because no established animal model representing the condition exists. We report that unilateral disinhibition of the nucleus accumbens (NAc) generates vocal tics in monkeys. Whole-brain PET imaging identified prominent, bilateral limbic cortico-subcortical activation. Local field potentials (LFPs) developed abnormal spikes in the NAc and the anterior cingulate cortex (ACC). Vocalization could occur without obvious LFP spikes, however, when phase-phase coupling of alpha oscillations were accentuated between the NAc, ACC, and the primary motor cortex. These findings contrasted with myoclonic motor tics induced by disinhibition of the dorsolateral putamen, where PET activity was confined to the ipsilateral sensorimotor system and LFP spikes always preceded motor tics. We propose that vocal tics emerge as a consequence of dysrhythmic alpha coupling between critical nodes in the limbic and motor networks. VIDEO ABSTRACT. PMID:26796690

  6. Gut-brain peptides in corticostriatal-limbic circuitry and alcohol use disorders

    PubMed Central

    Vadnie, Chelsea A.; Park, Jun Hyun; Abdel Gawad, Noha; Ho, Ada Man Choi; Hinton, David J.; Choi, Doo-Sup

    2014-01-01

    Peptides synthesized in endocrine cells in the gastrointestinal tract and neurons are traditionally considered regulators of metabolism, energy intake, and appetite. However, recent work has demonstrated that many of these peptides act on corticostriatal-limbic circuitry and, in turn, regulate addictive behaviors. Given that alcohol is a source of energy and an addictive substance, it is not surprising that increasing evidence supports a role for gut-brain peptides specifically in alcohol use disorders (AUD). In this review, we discuss the effects of several gut-brain peptides on alcohol-related behaviors and the potential mechanisms by which these gut-brain peptides may interfere with alcohol-induced changes in corticostriatal-limbic circuitry. This review provides a summary of current knowledge on gut-brain peptides focusing on five peptides: neurotensin, glucagon-like peptide 1, ghrelin, substance P, and neuropeptide Y. Our review will be helpful to develop novel therapeutic targets for AUD. PMID:25278825

  7. Limbic Metabolic Abnormalities in Remote Traumatic Brain Injury and Correlation With Psychiatric Morbidity and Social Functioning

    PubMed Central

    Capizzano, Arístides A.; Jorge, Ricardo E.; Robinson, Robert G.

    2013-01-01

    The aim of this study was to investigate limbic metabolic abnormalities in remote traumatic brain injury (TBI) and their psychiatric correlates. Twenty patients and 13 age-matched comparison subjects received complete psychiatric evaluation and brain MRI and MR spectroscopy at 3 Tesla. Patients had reduced NAA to creatine ratio in the left hippocampus relative to comparison subjects (mean=1.3 [SD=0.21] compared with mean=1.55 [SD=0.21]; F=10.73, df=1, 30, p=0.003), which correlated with the Social Functioning Examination scores (rs=−0.502, p=0.034). Furthermore, patients with mood disorders had reduced NAA to creatine ratio in the left cingulate relative to patients without mood disorders (1.47 compared with 1.68; F=3.393, df=3, 19, p=0.044). Remote TBI displays limbic metabolic abnormalities, which correlate to social outcome and psychiatric status. PMID:21037120

  8. Responses of Limbic and Extrapyramidal Substance P Systems to Nicotine Treatment

    PubMed Central

    Alburges, Mario E.; Frankel, Paul S.; Hoonakker, Amanda J.; Hanson, Glen R.

    2009-01-01

    Rationale Neuropeptides are linked to the psychopathology of stimulants of abuse, principally through dopamine mechanisms. Substance P (SP) is one of these neuropeptides and is associated with both limbic and extrapyramidal dopaminergic pathways and likely contributes to the pharmacology of these stimulants. The effects of nicotine on these dopamine systems has also been extensively studied, however, its effects on the associated SP pathways, have received little attention. Objectives In the present study, we elucidated the effects of nicotine treatment on limbic and extrapyramidal SP systems by measuring changes in associated SP tissue concentrations. Materials and methods Male Sprague-Dawley rats received (±) nicotine 4.0 mg/kg/day (0.8 mg/kg, intraperitoneally; five injections at 2-h intervals) in the presence or absence of selective dopamine D1 and D2 receptor antagonists or a nonselective nicotinic acetylcholine receptor antagonist. Results The nicotine treatment significantly but temporarily decreased substance P-like immunoreactivity (SPLI) content in the ventral tegmental area (VTA) and substantia nigra 12–18 h after drug exposure. The nicotine-mediated changes in SPLI were selectively blocked by pretreatment with mecamylamine as well as a dopamine D1, D2, or both receptor antagonists. Other brain areas that also selectively demonstrated nicotine-related declines in SPLI content included prefrontal cortex, the nucleus accumbens shell and the very posterior caudate. Conclusions These findings indicate that some limbic and basal ganglia SP systems are significantly affected by exposure to nicotine through processes mediated by nicotinic and dopaminergic receptors, suggesting a role for SP pathways in nicotine’s limbic and extrapyramidal effects. PMID:18773198

  9. Decreased limbic and increased fronto-parietal connectivity in unmedicated patients with obsessive-compulsive disorder.

    PubMed

    Göttlich, Martin; Krämer, Ulrike M; Kordon, Andreas; Hohagen, Fritz; Zurowski, Bartosz

    2014-11-01

    Obsessive-compulsive disorder (OCD) is characterized by recurrent intrusive thoughts and ritualized, repetitive behaviors, or mental acts. Convergent experimental evidence from neuroimaging and neuropsychological studies supports an orbitofronto-striato-thalamo-cortical dysfunction in OCD. Moreover, an over excitability of the amygdala and over monitoring of thoughts and actions involving the anterior cingulate, frontal and parietal cortex has been proposed as aspects of pathophysiology in OCD. We chose a data driven, graph theoretical approach to investigate brain network organization in 17 unmedicated OCD patients and 19 controls using resting-state fMRI. OCD patients showed a decreased connectivity of the limbic network to several other brain networks: the basal ganglia network, the default mode network, and the executive/attention network. The connectivity within the limbic network was also found to be decreased in OCD patients compared to healthy controls. Furthermore, we found a stronger connectivity of brain regions within the executive/attention network in OCD patients. This effect was positively correlated with disease severity. The decreased connectivity of limbic regions (amygdala, hippocampus) may be related to several neurocognitive deficits observed in OCD patients involving implicit learning, emotion processing and expectation, and processing of reward and punishment. Limbic disconnection from fronto-parietal regions relevant for (re)-appraisal may explain why intrusive thoughts become and/or remain threatening to patients but not to healthy subjects. Hyperconnectivity within the executive/attention network might be related to OCD symptoms such as excessive monitoring of thoughts and behavior as a dysfunctional strategy to cope with threat and uncertainty. PMID:25044747

  10. Methylphenidate attenuates limbic brain inhibition after cocaine-cues exposure in cocaine abusers.

    SciTech Connect

    Volkow, N.D.; Wang, G.; Volkow, N.D.; Wang, G.-J.; Tomasi, D.; Telang, F.; Fowler, J.S.; Pradhan, K.; Jayne, M.; Logan, J.; Goldstein, R.Z.; Alia-Klein, N.; Wong, C.T.

    2010-07-01

    Dopamine (phasic release) is implicated in conditioned responses. Imaging studies in cocaine abusers show decreases in striatal dopamine levels, which we hypothesize may enhance conditioned responses since tonic dopamine levels modulate phasic dopamine release. To test this we assessed the effects of increasing tonic dopamine levels (using oral methylphenidate) on brain activation induced by cocaine-cues in cocaine abusers. Brain metabolism (marker of brain function) was measured with PET and {sup 18}FDG in 24 active cocaine abusers tested four times; twice watching a Neutral video (nature scenes) and twice watching a Cocaine-cues video; each video was preceded once by placebo and once by methylphenidate (20 mg). The Cocaine-cues video increased craving to the same extent with placebo (68%) and with methylphenidate (64%). In contrast, SPM analysis of metabolic images revealed that differences between Neutral versus Cocaine-cues conditions were greater with placebo than methylphenidate; whereas with placebo the Cocaine-cues decreased metabolism (p<0.005) in left limbic regions (insula, orbitofrontal, accumbens) and right parahippocampus, with methylphenidate it only decreased in auditory and visual regions, which also occurred with placebo. Decreases in metabolism in these regions were not associated with craving; in contrast the voxel-wise SPM analysis identified significant correlations with craving in anterior orbitofrontal cortex (p<0.005), amygdala, striatum and middle insula (p<0.05). This suggests that methylphenidate's attenuation of brain reactivity to Cocaine-cues is distinct from that involved in craving. Cocaine-cues decreased metabolism in limbic regions (reflects activity over 30 minutes), which contrasts with activations reported by fMRI studies (reflects activity over 2-5 minutes) that may reflect long-lasting limbic inhibition following activation. Studies to evaluate the clinical significance of methylphenidate's blunting of cue-induced limbic

  11. Retroductive reasoning in a proposed subtype of partial seizures, evoked by limbic "kindling".

    PubMed

    Pontius, A A

    1995-02-01

    This analysis provides a specific example of the generally applicable process of creative delineation of a novel pattern while searching for an explanatory hypothesis for puzzling observations. In so doing, the neglected retroductive form of inference or abduction was used. Central to such a process is the delineation of a specific "generative mechanism" capable of uniting and explaining heretofore unexplained phenomena. Herein the neurophysiologically known mechanism of limbic seizure "kindling" is offered as a unifying explanation for a dozen bizarre phenomena, proposed as a new subtype of partial seizures, "Limbic Psychotic Trigger Reaction." This new syndrome has been proposed over 15 years in 17 male social loners. Upon encounter with an individualized stimulus, which revived in memory prior moderately hurtful experiences, these men suddenly committed motiveless, unplanned acts with flat affect, transient psychosis and autonomic arousal, showing no quantitative impairment of consciousness and so without memory loss for their perplexing homicidal acts (13 cases), firesetting (3 cases), or bank robbery (1 case). Events occurred in three phases reminiscent of seizures: (1) aura-like puzzlement, (2) transient ictus with a limbic release of predatory or defensive aggression (circa 20 min.), and (3) postictal inefficient actions, implicating a transient frontal lobe system dysfunction secondary to the limbic hyperactivation. The 17 men were of diverse backgrounds, but all without history of prior violence or severe emotional trauma. Seven of 17 had some abnormal tests at some time during their lives and eight known histories of typically overlooked closed-brain injury. Brain damage may facilitate seizure "kindling" but has been traditionally observed in mammals and in a few humans without such damage. PMID:7770594

  12. The metabolic effects of limbic leucotomy in Gilles de la Tourette syndrome.

    PubMed Central

    Sawle, G V; Lees, A J; Hymas, N F; Brooks, D J; Frackowiak, R S

    1993-01-01

    Regional cerebral oxygen metabolism was measured before and after limbic leucotomy in a patient with Gilles de la Tourette syndrome, obsessive compulsive disorder, and obsessional slowness. The preoperative scan showed hypermetabolism in the caudate nuclei, which normalised after operation. It is proposed that the beneficial effects of this operation on both tics and obsessive compulsive behaviour are mediated by disruption of abnormal neural activity in basal ganglia-thalamocortical loops. Images PMID:8410025

  13. Increased cortical-limbic anatomical network connectivity in major depression revealed by diffusion tensor imaging.

    PubMed

    Fang, Peng; Zeng, Ling-Li; Shen, Hui; Wang, Lubin; Li, Baojuan; Liu, Li; Hu, Dewen

    2012-01-01

    Magnetic resonance imaging studies have reported significant functional and structural differences between depressed patients and controls. Little attention has been given, however, to the abnormalities in anatomical connectivity in depressed patients. In the present study, we aim to investigate the alterations in connectivity of whole-brain anatomical networks in those suffering from major depression by using machine learning approaches. Brain anatomical networks were extracted from diffusion magnetic resonance images obtained from both 22 first-episode, treatment-naive adults with major depressive disorder and 26 matched healthy controls. Using machine learning approaches, we differentiated depressed patients from healthy controls based on their whole-brain anatomical connectivity patterns and identified the most discriminating features that represent between-group differences. Classification results showed that 91.7% (patients=86.4%, controls=96.2%; permutation test, p<0.0001) of subjects were correctly classified via leave-one-out cross-validation. Moreover, the strengths of all the most discriminating connections were increased in depressed patients relative to the controls, and these connections were primarily located within the cortical-limbic network, especially the frontal-limbic network. These results not only provide initial steps toward the development of neurobiological diagnostic markers for major depressive disorder, but also suggest that abnormal cortical-limbic anatomical networks may contribute to the anatomical basis of emotional dysregulation and cognitive impairments associated with this disease. PMID:23049910

  14. Stereotactic limbic leucotomy—a follow-up study of thirty patients

    PubMed Central

    Kelly, Desmond; Mitchell-Heggs, Nita

    1973-01-01

    This prospective study reports the results of stereotactic limbic leucotomy at a mean of 17 months following surgery. Clinical improvement had occurred in twenty-four (80%) of the patients, fifteen (50%) of them being symptom free or much improved. Fourteen of sixteen patients suffering from obsessional neurosis were improved, as were five of seven with chronic anxiety and the degree of improvement at 17 months was superior to that at 6 weeks. Psychometric scores of anxiety, obsessions and neuroticism were all significantly reduced at 17 months. The mean depression scores were also significantly reduced and this result was superior to that reported in a previous study of ‘free-hand’ operations. Adverse effects were not a problem following limbic leucotomy. Emotional blunting, disinhibition, post-operative epilepsy and excessive weight gain were not encountered, and intelligence was unaffected by the operation. Limbic leucotomy is a much more limited and precise procedure than older ‘free-hand’ operations which we have studied, but its therapeutic effects are comparable and in obsessional neurosis, superior. PMID:4618906

  15. Heritability of Subcortical and Limbic Brain Volume and Shape in Multiplex-Multigenerational Families with Schizophrenia

    PubMed Central

    Roalf, David R.; Vandekar, Simon N.; Almasy, Laura; Ruparel, Kosha; Satterthwaite, Theodore D.; Elliott, Mark A.; Podell, Jamie; Gallagher, Sean; Jackson, Chad T.; Prasad, Konasale; Wood, Joel; Pogue-Geile, Michael F.; Nimgaonkar, Vishwajit L.; Gur, Ruben C.; Gur, Raquel E.

    2014-01-01

    Background Brain abnormalities of subcortical and limbic nuclei are common in schizophrenia and variation in these structures is considered a putative endophenotype for the disorder. Multiplex-Multigenerational families afflicted by schizophrenia provide an opportunity to investigate the impact of shared genetic ancestry, but have not been previously examined to study structural brain abnormalities. Here we estimate the heritability of subcortical and hippocampal brain volumes in such families and the heritability of sub-regions using advanced shape analysis. Methods 439 participants from two sites completed 3-Tesla structural magnetic resonance imaging. They included 190 European-Americans from 32 Multiplex- Multigenerational families with schizophrenia and 249 healthy comparison subjects. Subcortical and hippocampal volume and shape were measured in 14 brain structures. Heritability was estimated for volume and shape. Results Volume and shape were heritable in families. Estimates of heritability in subcortical and limbic volumes ranged from 0.45 in the right hippocampus up to 0.84 in the left putamen. The shape of these structures was heritable (range: 0.40–0.49) and specific sub-regional shape estimates of heritability tended to exceed heritability estimates of volume alone. Conclusions These results demonstrate that volume and shape of subcortical and limbic brain structures are potential endophenotypic markers in schizophrenia. The specificity obtained using shape analysis may improve selection of imaging phenotypes that better reflect the underlying neurobiology. Our findings can aid in the identification of specific genetic targets that affect brain structure and function in schizophrenia. PMID:24976379

  16. Non-paraneoplastic limbic encephalitis and central nervous HHV-6B reactivation: Causality or coincidence?

    PubMed

    Niehusmann, Pitt; Widman, Guido; Eis-Hübinger, Anna M; Greschus, Susanne; Robens, Barbara K; Grote, Alexander; Becker, Albert J

    2016-08-01

    Autoantibody-related encephalopathies represent an important differential diagnosis in adult onset epilepsy. Here, we report the case of a 25-year-old patient with new-onset epilepsy and psychotic syndrome, who underwent biopsy resection for etiological classification. MRI analysis and neuropathological examination showed a T-lymphocytic dominated encephalitis with involvement of the limbic system. An indirect immunohistochemistry approach identified autoantibodies against glutamic acid decarboxylase (GAD) in cerebral spinal fluid and serum, which were confirmed by affinity purification / mass spectrometry analysis. Further examinations revealed evidence of chromosomally integrated human herpes virus type 6B (HHV-6B). However, astrocytic expression of HHV-6 lytic protein was detected by double immunofluorescence analysis. The cerebral expression of HHV-6 antigen, a clinical improvement under antiviral therapy as well as an initial finding of HHV-6 IgM antibodies strongly argue for an additional active HHV-6B infection. Review of the literature reveals singular reports of patients with GAD antibody-positive limbic encephalitis and central nervous system infections with HHV-6B. Since herpes simplex virus encephalitis has been recently reported as a trigger of N-methyl-D-aspartate receptor antibody encephalitis, it is tempting to speculate that HHV-6B infections may trigger a non-paraneoplastic form of limbic encephalitis in a parallel cascade. PMID:27431532

  17. Interactive effects of BDNF Val66Met genotype and trauma on limbic brain anatomy in childhood.

    PubMed

    Marusak, Hilary A; Kuruvadi, Nisha; Vila, Angela M; Shattuck, David W; Joshi, Shantanu H; Joshi, Anand A; Jella, Pavan K; Thomason, Moriah E

    2016-05-01

    Childhood trauma is a major precipitating factor in psychiatric disease. Emerging data suggest that stress susceptibility is genetically determined, and that risk is mediated by changes in limbic brain circuitry. There is a need to identify markers of disease vulnerability, and it is critical that these markers be investigated in childhood and adolescence, a time when neural networks are particularly malleable and when psychiatric disorders frequently emerge. In this preliminary study, we evaluated whether a common variant in the brain-derived neurotrophic factor (BDNF) gene (Val66Met; rs6265) interacts with childhood trauma to predict limbic gray matter volume in a sample of 55 youth high in sociodemographic risk. We found trauma-by-BDNF interactions in the right subcallosal area and right hippocampus, wherein BDNF-related gray matter changes were evident in youth without histories of trauma. In youth without trauma exposure, lower hippocampal volume was related to higher symptoms of anxiety. These data provide preliminary evidence for a contribution of a common BDNF gene variant to the neural correlates of childhood trauma among high-risk urban youth. Altered limbic structure in early life may lay the foundation for longer term patterns of neural dysfunction, and hold implications for understanding the psychiatric and psychobiological consequences of traumatic stress on the developing brain. PMID:26286685

  18. Continuous muscle activity, Morvan's syndrome and limbic encephalitis: ionic or non ionic disorders?

    PubMed

    Serratrice, G; Serratrice, J

    2011-06-01

    The early pathophysiologic study showed increasing evidence that autoimmunity is implicated in the pathogenesis of neuromyotonia. Antibodies to voltage gated potassium channel were detected in the serum of patients who had peripheral nerves hyperexcitability and also Morvan's disease or limbic encephalitis. These discoveries offered new approaches to treatments. Recently, antibodies previously attributed to VGKC recognise 2 surface antigens LGI1 and CASPR2 into the VGKC complex. Finally, VGKC antibodies are directed to 2 proteins the first one is a key hippocampic protein containing pre and post synaptic proteins. The second one CASPR2 is an hippocampic and paranodal protein. There clinical significance is different: hyperexcitability, limbic encephalitis without thymoma for LGI1, hyperexcitability, Morvan limbic encephalitis and frequent thymoma for CASPR2. In conclusion, the term NMT--LE--VGKC should be changed to NMT--LE with LGII and CASPR2 antibodies and classified as auto immune synaptic disorders. Mutations in genes encoding both these proteins are found in hereditary epilepsy and other syndromes. Various potassium channelopathies are closely linked to Morvan's syndromes. A new classification of antibodies will be necessary. PMID:21842591

  19. Effects of isomers of apomorphines on dopamine receptors in striatal and limbic tissue of rat brain

    SciTech Connect

    Kula, N.S.; Baldessarini, R.J.; Bromley, S.; Neumeyer, J.L.

    1985-09-16

    The optical isomers of apomorphine (APO) and N-propylnorapomorphine (NPA) were interacted with three biochemical indices of dopamine (Da) receptors in extrapyramidal and limbic preparations of rat brain tissues. There were consistent isomeric preferences for the R(-) configuration of both DA analogs in stimulation adenylate cyclase (D-1 sites) and in competing for high affinity binding of /sup 3/H-spiroperidol (D-2 sites) and of /sup 3/H-ADTN (DA agonist binding sites) in striatal tissue, with lesser isomeric differences in the limbic tissue. The S(+) apomorphines did not inhibit stimulation of adenylate cyclase by DA. The tendency for greater activity of higher apparent affinity of R(-) apomorphines in striatum may reflect the evidently greater abundance of receptor sites in that region. There were only small regional differences in interactions of the apomorphine isomers with all three receptor sites, except for a strong preference of (-)NPA for striatal D-2 sites. These results do not parallel our recent observations indicating potent and selective antidopaminergic actions of S(+) apomorphines in the rat limbic system. They suggest caution in assuming close parallels between current biochemical functional, especially behavioral, methods of evaluating dopamine receptors of mammalian brain.

  20. Delayed noradrenergic activation in the dorsal hippocampus promotes the long-term persistence of extinguished fear.

    PubMed

    Chai, Ning; Liu, Jian-Feng; Xue, Yan-Xue; Yang, Chang; Yan, Wei; Wang, Hui-Min; Luo, Yi-Xiao; Shi, Hai-Shui; Wang, Ji-Shi; Bao, Yan-Ping; Meng, Shi-Qiu; Ding, Zeng-Bo; Wang, Xue-Yi; Lu, Lin

    2014-07-01

    Fear extinction has been extensively studied, but little is known about the molecular processes that underlie the persistence of extinction long-term memory (LTM). We found that microinfusion of norepinephrine (NE) into the CA1 area of the dorsal hippocampus during the early phase (0 h) after extinction enhanced extinction LTM at 2 and 14 days after extinction. Intra-CA1 infusion of NE during the late phase (12 h) after extinction selectively promoted extinction LTM at 14 days after extinction that was blocked by the β-receptor antagonist propranolol, protein kinase A (PKA) inhibitor Rp-cAMPS, and protein synthesis inhibitors anisomycin and emetine. The phosphorylation levels of PKA, cyclic adenosine monophosphate response element-binding protein (CREB), GluR1, and the membrane GluR1 level were increased by NE during the late phase after extinction that was also blocked by propranolol and Rp-cAMPS. These results suggest that the enhancement of extinction LTM persistence induced by NE requires the activation of the β-receptor/PKA/CREB signaling pathway and membrane GluR1 trafficking. Moreover, extinction increased the phosphorylation levels of Erk1/2, CREB, and GluR1, and the membrane GluR1 level during the late phase, and anisomycin/emetine alone disrupted the persistence of extinction LTM, indicating that the persistence of extinction LTM requires late-phase protein synthesis in the CA1. Propranolol and Rp-cAMPS did not completely disrupt the persistence of extinction LTM, suggesting that another β-receptor/PKA-independent mechanism underlies the persistence of extinction LTM. Altogether, our results showed that enhancing hippocampal noradrenergic activity during the late phase after extinction selectively promotes the persistence of extinction LTM. PMID:24553734

  1. Antidepressant-like activity of dehydrozingerone: involvement of the serotonergic and noradrenergic systems.

    PubMed

    Martinez, Débora M; Barcellos, Angelita; Casaril, Angela M; Savegnago, Lucielli; Lernardão, Eder J

    2014-12-01

    Dehydrozingerone (DHZ) is a phenolic compound isolated from ginger rhizomes (Zingiber officinale). It is known for its diverse spectrum of biological activities as an antioxidant, anti-inflammatory and antitumor compound. The present study was designed to assess the antidepressant effect of DHZ and the involvement of the monoaminergic system and to evaluate its in vitro antioxidant activity in the hippocampus, cortex and cerebellum of mice. For this study, the tail suspension test (TST), forced swim test (FST) and yohimbine lethality test were performed. DHZ administered orally 30min prior to testing reduced the immobility time in the TST (1-40mg/kg) and the FST (10-40mg/kg), with no change in locomotor activity in the open field test. The antidepressant-like effect of DHZ (1mg/kg) was prevented by ketanserin (1mg/kg, i.p.; a 5-HT2A/2C receptor antagonist), ondansetron (1mg/kg, i.p.; a 5-HT3 receptor antagonist), prazosin (1mg/kg, i.p., an α1-adrenoceptor antagonist) and yohimbine (1mg/kg, i.p., an α2-adrenoceptor antagonist) pretreatments. Furthermore, DHZ administered at doses of 10 and 20mg/kg increased the lethality of yohimbine (35mg/kg, i.p.). DHZ had antioxidant activity on in vitro lipid peroxidation induced by sodium nitroprusside in all brain regions tested. The results revealed that DHZ has a potent antidepressant effect, which seems to involve the serotonergic and noradrenergic systems. PMID:25449795

  2. Delayed Noradrenergic Activation in the Dorsal Hippocampus Promotes the Long-Term Persistence of Extinguished Fear

    PubMed Central

    Chai, Ning; Liu, Jian-Feng; Xue, Yan-Xue; Yang, Chang; Yan, Wei; Wang, Hui-Min; Luo, Yi-Xiao; Shi, Hai-Shui; Wang, Ji-Shi; Bao, Yan-Ping; Meng, Shi-Qiu; Ding, Zeng-Bo; Wang, Xue-Yi; Lu, Lin

    2014-01-01

    Fear extinction has been extensively studied, but little is known about the molecular processes that underlie the persistence of extinction long-term memory (LTM). We found that microinfusion of norepinephrine (NE) into the CA1 area of the dorsal hippocampus during the early phase (0 h) after extinction enhanced extinction LTM at 2 and 14 days after extinction. Intra-CA1 infusion of NE during the late phase (12 h) after extinction selectively promoted extinction LTM at 14 days after extinction that was blocked by the β-receptor antagonist propranolol, protein kinase A (PKA) inhibitor Rp-cAMPS, and protein synthesis inhibitors anisomycin and emetine. The phosphorylation levels of PKA, cyclic adenosine monophosphate response element-binding protein (CREB), GluR1, and the membrane GluR1 level were increased by NE during the late phase after extinction that was also blocked by propranolol and Rp-cAMPS. These results suggest that the enhancement of extinction LTM persistence induced by NE requires the activation of the β-receptor/PKA/CREB signaling pathway and membrane GluR1 trafficking. Moreover, extinction increased the phosphorylation levels of Erk1/2, CREB, and GluR1, and the membrane GluR1 level during the late phase, and anisomycin/emetine alone disrupted the persistence of extinction LTM, indicating that the persistence of extinction LTM requires late-phase protein synthesis in the CA1. Propranolol and Rp-cAMPS did not completely disrupt the persistence of extinction LTM, suggesting that another β-receptor/PKA-independent mechanism underlies the persistence of extinction LTM. Altogether, our results showed that enhancing hippocampal noradrenergic activity during the late phase after extinction selectively promotes the persistence of extinction LTM. PMID:24553734

  3. Effects of Propranolol, a β-noradrenergic Antagonist, on Memory Consolidation and Reconsolidation in Mice

    PubMed Central

    Villain, Hélène; Benkahoul, Aïcha; Drougard, Anne; Lafragette, Marie; Muzotte, Elodie; Pech, Stéphane; Bui, Eric; Brunet, Alain; Birmes, Philippe; Roullet, Pascal

    2016-01-01

    Memory reconsolidation impairment using the β-noradrenergic receptor blocker propranolol is a promising novel treatment avenue for patients suffering from pathogenic memories, such as post-traumatic stress disorder (PTSD). However, in order to better inform targeted treatment development, the effects of this compound on memory need to be better characterized via translational research. We examined the effects of systemic propranolol administration in mice undergoing a wide range of behavioral tests to determine more specifically which aspects of the memory consolidation and reconsolidation are impaired by propranolol. We found that propranolol (10 mg/kg) affected memory consolidation in non-aversive tasks (object recognition and object location) but not in moderately (Morris water maze (MWM) to highly (passive avoidance, conditioned taste aversion) aversive tasks. Further, propranolol impaired memory reconsolidation in the most and in the least aversive tasks, but not in the moderately aversive task, suggesting its amnesic effect was not related to task aversion. Moreover, in aquatic object recognition and location tasks in which animals were forced to behave (contrary to the classic versions of the tasks); propranolol did not impair memory reconsolidation. Taken together our results suggest that the memory impairment observed after propranolol administration may result from a modification of the emotional valence of the memory rather than a disruption of the contextual component of the memory trace. This is relevant to the use of propranolol to block memory reconsolidation in individuals with PTSD, as such a treatment would not erase the traumatic memory but only reduce the emotional valence associated with this event. PMID:27014009

  4. Transcription factor activating protein 2 beta (TFAP2B) mediates noradrenergic neuronal differentiation in neuroblastoma.

    PubMed

    Ikram, Fakhera; Ackermann, Sandra; Kahlert, Yvonne; Volland, Ruth; Roels, Frederik; Engesser, Anne; Hertwig, Falk; Kocak, Hayriye; Hero, Barbara; Dreidax, Daniel; Henrich, Kai-Oliver; Berthold, Frank; Nürnberg, Peter; Westermann, Frank; Fischer, Matthias

    2016-02-01

    Neuroblastoma is an embryonal pediatric tumor that originates from the developing sympathetic nervous system and shows a broad range of clinical behavior, ranging from fatal progression to differentiation into benign ganglioneuroma. In experimental neuroblastoma systems, retinoic acid (RA) effectively induces neuronal differentiation, and RA treatment has been therefore integrated in current therapies. However, the molecular mechanisms underlying differentiation are still poorly understood. We here investigated the role of transcription factor activating protein 2 beta (TFAP2B), a key factor in sympathetic nervous system development, in neuroblastoma pathogenesis and differentiation. Microarray analyses of primary neuroblastomas (n = 649) demonstrated that low TFAP2B expression was significantly associated with unfavorable prognostic markers as well as adverse patient outcome. We also found that low TFAP2B expression was strongly associated with CpG methylation of the TFAP2B locus in primary neuroblastomas (n = 105) and demethylation with 5-aza-2'-deoxycytidine resulted in induction of TFAP2B expression in vitro, suggesting that TFAP2B is silenced by genomic methylation. Tetracycline inducible re-expression of TFAP2B in IMR-32 and SH-EP neuroblastoma cells significantly impaired proliferation and cell cycle progression. In IMR-32 cells, TFAP2B induced neuronal differentiation, which was accompanied by up-regulation of the catecholamine biosynthesizing enzyme genes DBH and TH, and down-regulation of MYCN and REST, a master repressor of neuronal genes. By contrast, knockdown of TFAP2B by lentiviral transduction of shRNAs abrogated RA-induced neuronal differentiation of SH-SY5Y and SK-N-BE(2)c neuroblastoma cells almost completely. Taken together, our results suggest that TFAP2B is playing a vital role in retaining RA responsiveness and mediating noradrenergic neuronal differentiation in neuroblastoma. PMID:26598443

  5. Determination of the role of noradrenergic and 5-hydroxytryptaminergic neurones in postsynaptic alpha 2-adrenoceptor desensitization by desipramine and ECS.

    PubMed Central

    Heal, D. J.; Prow, M. R.; Buckett, W. R.

    1991-01-01

    1. Experiments were conducted to determine the respective roles which noradrenergic and 5-hydroxytryptaminergic neurones play in the down-regulation of postsynaptic alpha 2-adrenoceptors by desipramine and electroconvulsive shock (ECS). The functional status of these receptors was monitored by use of clonidine-induced mydriasis in conscious mice. 2. Mydriasis to clonidine (0.1 mg kg-1, i.p.) was markedly attenuated by administration of either desipramine (10 mg kg-1, i.p.) for 14 days or ECS (200 V, 2s) given five times over ten days confirming our previous observations. 3. The neurotoxin, DSP-4 (100 mg kg-1, i.p. X 2), reduced brain noradrenaline levels by 64% and abolished the mydriasis induced by the noradrenaline releasing agent and reuptake inhibitor, methamphetamine, without significantly altering the response to clonidine, confirming our earlier results. This lesion prevented the attenuation of clonidine mydriasis by repeated administration of desipramine, but not ECS. 4. Lesioning of central 5-hydroxytryptaminergic neurones with 5,7-dihydroxytryptamine (75 micrograms, i.c.v.) had no influence on the reduction in clonidine mydriasis produced by repeated administration of either desipramine or ECS. 5. Since noradrenergic neurones are essential for the desensitization of postsynaptic alpha 2-adrenoceptors by desipramine, it indicates that this effect is probably the result of increased synaptic noradrenaline levels. This mechanism is not responsible for the change induced by ECS because this adaptation is independent of an intact noradrenergic input. 5-HT-containing neurones do not play a permissive role in the down-regulation of postsynaptic alpha 2-adrenoceptors by either antidepressant treatment. PMID:1655144

  6. Reduced activity of the noradrenergic system in the paraventricular nucleus at the end of pregnancy: implications for stress hyporesponsiveness.

    PubMed

    Douglas, A J; Meddle, S L; Toschi, N; Bosch, O J; Neumann, I D

    2005-01-01

    We investigated whether changes in noradrenaline neurotransmission in the hypothalamus could explain the hyporesponsiveness of the hypothalamic-pituitary-adrenal (HPA) axis in late pregnancy. Noradrenaline release within the hypothalamic paraventricular nucleus in response to swim stress, as estimated by microdialysis and high-performance liquid chromatography, was lower in 20-day pregnant rats compared to virgin rats. Driving a central noradrenergic pathway using intravenous cholecystokinin increased adrenocorticotropic hormone (ACTH) secretion in virgin rats, but the response was significantly less in 16-day and 20-day pregnant rats. Thus, the activity of noradrenergic inputs to the paraventricular nucleus and the HPA axis is attenuated in late pregnancy. The sensitivity of the HPA axis to noradrenaline in pregnancy was investigated by intracerebroventricular administration of an alpha1-receptor antagonist, benoxathian, before and during exposure to swim stress. In virgin rats, benoxathian increased basal and stress-induced ACTH secretion, but in late pregnant rats the benoxathian effects were attenuated, indicating reduced sensitivity of the HPA axis to noradrenaline neurotransmission and/or the inability of the system to become disinhibited at this time. alpha1A-adrenoreceptor mRNA expression in the parvocellular and magnocellular paraventricular nucleus, measured by in situ hybridisation, was decreased in late pregnant compared to virgin rats. Additionally, blocking endogenous opioid inhibition with naloxone pretreatment restored the ACTH secretory response to cholecystokinin in pregnant rats. Thus, in late pregnancy, there is reduced noradrenergic input to the paraventricular nucleus and reduced alpha1A-receptor expression in the paraventricular nucleus, both of which may contribute to the reduced responsiveness of the HPA axis in pregnancy. PMID:15720474

  7. Interactions between brainstem noradrenergic neurons and the nucleus accumbens shell in modulating memory for emotionally arousing events

    PubMed Central

    Kerfoot, Erin C.; Williams, Cedric L.

    2011-01-01

    The nucleus accumbens shell (NAC) receives axons containing dopamine-β-hydroxylase that originate from brainstem neurons in the nucleus of the solitary tract (NTS). Recent findings show that memory enhancement produced by stimulating NTS neurons after learning may involve interactions with the NAC. However, it is unclear whether these mnemonic effects are mediated by norepinephrine (NE) release from NTS terminals onto NAC neurons. The present studies approached this question by examining the contribution of NAC α-noradrenergic receptors in mediating this effect and assessed whether glutamatergic activation of the NTS alters NE concentrations in the NAC. Rats were trained for 6 d to drink from a water spout located at the end of an inhibitory avoidance chamber. On day 7, a 0.35-mA footshock was initiated once the rat approached the spout and remained active until it escaped into the neutral compartment. Blockade of α-noradrenergic receptors in the NAC with phentolamine (0.5 µg/0.5 µL) attenuated memory enhancement produced by glutamatergic (50 ng/0.5 µL) infusion on NTS neurons (P < 0.01). Experiment 2 used in vivo microdialysis to assess whether glutamate activation of NTS alters NAC NE concentrations. NE levels were unchanged by NTS infusion of phosphate-buffered saline (PBS) or low dose glutamate (50 ng/0.5 µL) but elevated significantly (P < 0.05) by combining the same dose with the footshock (0.35 mA, 2 sec) given in Study 1 or infusion of (100 ng/0.5 µL) glutamate alone. Findings demonstrate that NE released from NTS terminals enhances representations in memory by acting on α-noradrenergic receptors within the NAC. PMID:21602321

  8. Noradrenergic stimulation modulates activation of extinction-related brain regions and enhances contextual extinction learning without affecting renewal

    PubMed Central

    Lissek, Silke; Glaubitz, Benjamin; Güntürkün, Onur; Tegenthoff, Martin

    2015-01-01

    Renewal in extinction learning describes the recovery of an extinguished response if the extinction context differs from the context present during acquisition and recall. Attention may have a role in contextual modulation of behavior and contribute to the renewal effect, while noradrenaline (NA) is involved in attentional processing. In this functional magnetic resonance imaging (fMRI) study we investigated the role of the noradrenergic system for behavioral and brain activation correlates of contextual extinction and renewal, with a particular focus upon hippocampus and ventromedial prefrontal cortex (PFC), which have crucial roles in processing of renewal. Healthy human volunteers received a single dose of the NA reuptake inhibitor atomoxetine prior to extinction learning. During extinction of previously acquired cue-outcome associations, cues were presented in a novel context (ABA) or in the acquisition context (AAA). In recall, all cues were again presented in the acquisition context. Atomoxetine participants (ATO) showed significantly faster extinction compared to placebo (PLAC). However, atomoxetine did not affect renewal. Hippocampal activation was higher in ATO during extinction and recall, as was ventromedial PFC activation, except for ABA recall. Moreover, ATO showed stronger recruitment of insula, anterior cingulate, and dorsolateral/orbitofrontal PFC. Across groups, cingulate, hippocampus and vmPFC activity during ABA extinction correlated with recall performance, suggesting high relevance of these regions for processing the renewal effect. In summary, the noradrenergic system appears to be involved in the modification of established associations during extinction learning and thus has a role in behavioral flexibility. The assignment of an association to a context and the subsequent decision on an adequate response, however, presumably operate largely independently of noradrenergic mechanisms. PMID:25745389

  9. Noradrenergic activation of the basolateral amygdala enhances object recognition memory and induces chromatin remodeling in the insular cortex

    PubMed Central

    Beldjoud, Hassiba; Barsegyan, Areg; Roozendaal, Benno

    2015-01-01

    It is well established that arousal-induced memory enhancement requires noradrenergic activation of the basolateral complex of the amygdala (BLA) and modulatory influences on information storage processes in its many target regions. While this concept is well accepted, the molecular basis of such BLA effects on neural plasticity changes within other brain regions remains to be elucidated. The present study investigated whether noradrenergic activation of the BLA after object recognition training induces chromatin remodeling through histone post-translational modifications in the insular cortex (IC), a brain region that is importantly involved in object recognition memory. Male Sprague—Dawley rats were trained on an object recognition task, followed immediately by bilateral microinfusions of norepinephrine (1.0 μg) or saline administered into the BLA. Saline-treated control rats exhibited poor 24-h retention, whereas norepinephrine treatment induced robust 24-h object recognition memory. Most importantly, this memory-enhancing dose of norepinephrine induced a global reduction in the acetylation levels of histone H3 at lysine 14, H2B and H4 in the IC 1 h later, whereas it had no effect on the phosphorylation of histone H3 at serine 10 or tri-methylation of histone H3 at lysine 27. Norepinephrine administered into the BLA of non-trained control rats did not induce any changes in the histone marks investigated in this study. These findings indicate that noradrenergic activation of the BLA induces training-specific effects on chromatin remodeling mechanisms, and presumably gene transcription, in its target regions, which may contribute to the understanding of the molecular mechanisms of stress and emotional arousal effects on memory consolidation. PMID:25972794

  10. Development of glucocorticoid receptor regulation in the rat forebrain: Implications for adverse effects of glucocorticoids in preterm infants

    EPA Science Inventory

    Glucocorticoids are the consensus treatment to avoid respiratory distress in preterm infants but there is accumulating evidence that these agents evoke long-term neurobehavioral deficits. Earlier, we showed that the developing rat forebrain is far more sensitive to glucocorticoi...

  11. Fezf2 promotes neuronal differentiation through localised activation of Wnt/β-catenin signalling during forebrain development

    PubMed Central

    Zhang, Siwei; Li, Jingjing; Lea, Robert; Vleminckx, Kris; Amaya, Enrique

    2014-01-01

    Brain regionalisation, neuronal subtype diversification and circuit connectivity are crucial events in the establishment of higher cognitive functions. Here we report the requirement for the transcriptional repressor Fezf2 for proper differentiation of neural progenitor cells during the development of the Xenopus forebrain. Depletion of Fezf2 induces apoptosis in postmitotic neural progenitors, with concomitant reduction in forebrain size and neuronal differentiation. Mechanistically, we found that Fezf2 stimulates neuronal differentiation by promoting Wnt/β-catenin signalling in the developing forebrain. In addition, we show that Fezf2 promotes activation of Wnt/β-catenin signalling by repressing the expression of two negative regulators of Wnt signalling, namely lhx2 and lhx9. Our findings suggest that Fezf2 plays an essential role in controlling when and where neuronal differentiation occurs within the developing forebrain and that it does so by promoting local Wnt/β-catenin signalling via a double-repressor model. PMID:25468942

  12. Overexpression of the Type 1 Adenylyl Cyclase in the Forebrain Leads to Deficits of Behavioral Inhibition

    PubMed Central

    Cao, Hong; Saraf, Amit; Zweifel, Larry S.

    2015-01-01

    The type 1 adenylyl cyclase (AC1) is an activity-dependent, calcium-stimulated adenylyl cyclase expressed in the nervous system that is implicated in memory formation. We examined the locomotor activity, and impulsive and social behaviors of AC1+ mice, a transgenic mouse strain overexpressing AC1 in the forebrain. Here we report that AC1+ mice exhibit hyperactive behaviors and demonstrate increased impulsivity and reduced sociability. In contrast, AC1 and AC8 double knock-out mice are hypoactive, and exhibit increased sociability and reduced impulsivity. Interestingly, the hyperactivity of AC1+ mice can be corrected by valproate, a mood-stabilizing drug. These data indicate that increased expression of AC1 in the forebrain leads to deficits in behavioral inhibition. PMID:25568126

  13. The ancestral role of nodal signalling in breaking L/R symmetry in the vertebrate forebrain.

    PubMed

    Lagadec, Ronan; Laguerre, Laurent; Menuet, Arnaud; Amara, Anis; Rocancourt, Claire; Péricard, Pierre; Godard, Benoît G; Rodicio, Maria Celina; Rodriguez-Moldes, Isabel; Mayeur, Hélène; Rougemont, Quentin; Mazan, Sylvie; Boutet, Agnès

    2015-01-01

    Left-right asymmetries in the epithalamic region of the brain are widespread across vertebrates, but their magnitude and laterality varies among species. Whether these differences reflect independent origins of forebrain asymmetries or taxa-specific diversifications of an ancient vertebrate feature remains unknown. Here we show that the catshark Scyliorhinus canicula and the lampreys Petromyzon marinus and Lampetra planeri exhibit conserved molecular asymmetries between the left and right developing habenulae. Long-term pharmacological treatments in these species show that nodal signalling is essential to their generation, rather than their directionality as in teleosts. Moreover, in contrast to zebrafish, habenular left-right differences are observed in the absence of overt asymmetry of the adjacent pineal field. These data support an ancient origin of epithalamic asymmetry, and suggest that a nodal-dependent asymmetry programme operated in the forebrain of ancestral vertebrates before evolving into a variable trait in bony fish. PMID:25819227

  14. Reduced forebrain serotonin transmission is causally involved in the development of compulsive cocaine seeking in rats.

    PubMed

    Pelloux, Yann; Dilleen, Ruth; Economidou, Daina; Theobald, David; Everitt, Barry J

    2012-10-01

    Whereas the majority of cocaine users quit as they experience the negative consequences of drug use, some lose control over their drug taking and compulsively seek drugs. We report that 20% of rats compulsively seek cocaine despite intermittent negative outcomes after escalating their cocaine self-administration. This compulsive subgroup showed marked reductions in forebrain serotonin utilization; increasing serotonin transmission reduced their compulsive cocaine seeking. Depleting forebrain serotonin induced compulsive cocaine seeking in rats with a limited cocaine taking history; this was reversed by systemic treatment with a 5-hydroxytryptamine (5-HT2C) receptor agonist and mimicked by systemic treatment with a 5-HT2C receptor antagonist in intact animals. These results indicate the causal involvement of reduced serotoninergic transmission in the emergence of compulsive drug seeking after a long cocaine-taking history. PMID:22763621

  15. ADAR1 and ADAR2 Expression and Editing Activity during Forebrain Development

    PubMed Central

    Jacobs, Michelle M.; Fogg, Rachel L.; Emeson, Ronald B.; Stanwood, Gregg D.

    2009-01-01

    The conversion of adenosine-to-inosine within RNA transcripts is regulated by the ADAR family of enzymes. Little is known regarding the developmental expression of ADAR family members or the mechanisms responsible for the specific patterns of editing observed for ADAR substrates. We have examined the spatiotemporal expression patterns for ADAR1 and ADAR2 in mouse forebrain. ADAR1 and ADAR2 are broadly distributed in most regions of the mouse forebrain by P0, including the cerebral cortex, hippocampus, and diencephalon. High expression levels were maintained into adulthood. Co-localization studies demonstrated ADAR1 and ADAR2 expression in neurons but not astrocytes. Editing for specific ADAR mRNA targets precedes high expression of ADAR proteins, suggesting that region-specific differences in editing patterns may not be mediated solely by ADAR expression levels. PMID:19325227

  16. Receptors for GRP/bombesin-like peptides in the rat forebrain

    SciTech Connect

    Wolf, S.S.; Moody, T.W.

    1985-01-01

    Binding sites in the rat forebrain were characterized using ( SVI-Tyr4)bombesin as a receptor probe. Pharmacology experiments indicate that gastrin releasing peptide (GRP) and the GRP fragments GRP as well as Ac-GRP inhibited radiolabeled (Tyr4)bombesin binding with high affinity. Biochemistry experiments indicated that heat, N-ethyl maleimide or trypsin greatly reduced radiolabeled (Tyr4)bombesin binding. Also, autoradiographic studies indicated that highest grain densities were present in the stria terminalis, periventricular and suprachiasmatic nucleus of the hypothalamus, dorsomedial and rhomboid thalamus, dentate gyrus, hippocampus and medial amygdaloid nucleus. The data suggest that CNS protein receptors, which are discretely distributed in the rat forebrain, may mediate the action of endogenous GRP/bombesin-like peptides.

  17. Forebrain-Specific Loss of BMPRII in Mice Reduces Anxiety and Increases Object Exploration

    PubMed Central

    McBrayer, Zofeyah L.; Dimova, Jiva; Pisansky, Marc T.; Sun, Mu; Beppu, Hideyuki; Gewirtz, Jonathan C.; O’Connor, Michael B.

    2015-01-01

    To investigate the role of Bone Morphogenic Protein Receptor Type II (BMPRII) in learning, memory, and exploratory behavior in mice, a tissue-specific knockout of BMPRII in the post-natal hippocampus and forebrain was generated. We found that BMPRII mutant mice had normal spatial learning and memory in the Morris water maze, but showed significantly reduced swimming speeds with increased floating behavior. Further analysis using the Porsolt Swim Test to investigate behavioral despair did not reveal any differences in immobility between mutants and controls. In the Elevated Plus Maze, BMPRII mutants and Smad4 mutants showed reduced anxiety, while in exploratory tests, BMPRII mutants showed more interest in object exploration. These results suggest that loss of BMPRII in the mouse hippocampus and forebrain does not disrupt spatial learning and memory encoding, but instead impacts exploratory and anxiety-related behaviors. PMID:26444546

  18. Delta FosB and AP-1-mediated transcription modulate cannabinoid CB1 receptor signaling and desensitization in striatal and limbic brain regions

    PubMed Central

    Lazenka, Matthew F.; David, Bethany G.; Lichtman, Aron H.; Nestler, Eric J.; Selley, Dana E.; Sim-Selley, Laura J.

    2014-01-01

    Repeated Δ9-tetrahydrocannabinol (THC) administration produces cannabinoid type 1 receptor (CB1R) desensitization and downregulation, as well as tolerance to its in vivo pharmacological effects. However, the magnitude of CB1R desensitization varies by brain region, with CB1Rs in the striatum and its output nuclei undergoing less desensitization than other regions. A growing body of data indicates that regional differences in CB1R desensitization are produced, in part, by THC-mediated induction of the stable transcription factor, ΔFosB, and subsequent regulation of CB1Rs. The purpose of the present study was to determine whether THC-mediated induction of ΔFosB in the striatum inhibits CB1R desensitization in the striatum and output nuclei. This hypothesis was tested using bitransgenic mice with inducible expression of ΔFosB or ΔcJun, a dominant negative inhibitor of AP-1-mediated transcription, in specific forebrain regions. Mice were treated repeatedly with escalating doses of THC or vehicle for 6.5 days, and CB1R-mediated G-protein activation was assessed using CP55,940-stimulated [35S]GTPγS autoradiography. Overexpression of ΔFosB in striatal dopamine type 1 receptor-containing (D1R) medium spiny neurons (MSNs) attenuated CB1R desensitization in the substantia nigra, ventral tegmental area (VTA) and amygdala. Expression of ΔcJun in striatal D1R- and dopamine type 2 receptor (D2R)-containing MSNs enhanced CB1R desensitization in the caudate-putamen and attenuated desensitization in the hippocampus and VTA. THC-mediated in vivo pharmacological effects were then assessed in ΔcJun-expressing mice. Tolerance to THC-mediated hypomotility was enhanced in ΔcJun-expressing mice. These data reveal that ΔFosB and possibly other AP-1 binding proteins regulate CB1R signaling and adaptation in the striatum and limbic system. PMID:25093286

  19. Brain-derived neurotrophic factor signaling is altered in the forebrain of Engrailed-2 knockout mice.

    PubMed

    Zunino, G; Messina, A; Sgadò, P; Baj, G; Casarosa, S; Bozzi, Y

    2016-06-01

    Engrailed-2 (En2), a homeodomain transcription factor involved in regionalization and patterning of the midbrain and hindbrain regions has been associated to autism spectrum disorders (ASDs). En2 knockout (En2(-/-)) mice show ASD-like features accompanied by a significant loss of GABAergic subpopulations in the hippocampus and neocortex. Brain-derived neurotrophic factor (BDNF) is a crucial factor for the postnatal development of forebrain GABAergic neurons, and altered GABA signaling has been hypothesized to underlie the symptoms of ASD. Here we sought to determine whether interneuron loss in the En2(-/-) forebrain might be related to altered expression of BDNF and its signaling receptors. We first evaluated the expression of different BDNF mRNA isoforms in the neocortex and hippocampus of wild-type (WT) and En2(-/-) mice. Quantitative RT-PCR showed a marked down-regulation of several splicing variants of BDNF mRNA in the neocortex but not hippocampus of adult En2(-/-) mice, as compared to WT controls. Accordingly, levels of mature BDNF protein were lower in the neocortex but not hippocampus of En2(-/-) mice, as compared to WT. Increased levels of phosphorylated TrkB and decreased levels of p75 receptor were also detected in the neocortex of mutant mice. Accordingly, the expression of low density lipoprotein receptor (LDLR) and RhoA, two genes regulated via p75 was significantly altered in forebrain areas of mutant mice. These data indicate that BDNF signaling alterations might be involved in the anatomical changes observed in the En2(-/-) forebrain and suggest a pathogenic role of altered BDNF signaling in this mouse model of ASD. PMID:26987954

  20. Stereotaxic probabilistic maps of the magnocellular cell groups in human basal forebrain

    PubMed Central

    Zaborszky, L.; Hoemke, L.; Mohlberg, H.; Schleicher, A.; Amunts, K.; Zilles, K.

    2008-01-01

    The basal forebrain contains several interdigitating anatomical structures, including the diagonal band of Broca, the basal nucleus of Meynert, the ventral striatum, and also cell groups underneath the globus pallidus that bridge the centromedial amygdala to the bed nucleus of the stria terminalis. Among the cell populations, the magnocellular, cholinergic corticopetal projection neurons have received particular attention due to their loss in Alzheimer’s disease. In MRI images, the precise delineation of these structures is difficult due to limited spatial resolution and contrast. Here, using microscopic delineations in ten human postmortem brains, we present stereotaxic probabilistic maps of the basal forebrain areas containing the magnocellular cell groups. Cytoarchitectonic mapping was performed in silver stained histological serial sections. The positions and the extent of the magnocellular cell groups within the septum (Ch1-2), the horizontal limb of the diagonal band (Ch3), and in the sublenticular part of the basal forebrain (Ch4) were traced in high-resolution digitized histological sections, 3D reconstructed, and warped to the reference space of the MNI single subject brain. The superposition of the cytoarchitectonic maps in the MNI brain shows the intersubject variability of the various Ch compartments and their stereotaxic position relative to other brain structures. Both the right and left Ch4 regions showed significantly smaller volumes when age was considered as a covariate. Probabilistic maps of compartments of the basal forebrain magnocellular system are now available as an open source reference for correlation with fMRI, PET, and structural MRI data of the living human brain. PMID:18585468

  1. Terminal field specificity of forebrain efferent axons to brainstem gustatory nuclei.

    PubMed

    Kang, Yi; Lundy, Robert F

    2009-01-12

    Rostral forebrain structures like the gustatory cortex (GC), bed nucleus of the stria terminalis (BNST), central nucleus of the amygdala (CeA), and lateral hypothalamus (LH) send projections to the nucleus of solitary tract (NST) and the parabrachial nucleus (PBN) that modulate taste-elicited responses. However, the proportion of forebrain-induced excitatory and inhibitory effects often differs when taste cell recording changes from the NST to the PBN. The present study investigated whether this descending influence originates from a shared or distinct population of forebrain neurons. Under electrophysiological guidance, the retrograde tracers fast blue (FB) and fluorogold (FG) or green (GFB) and red (RFB) fluorescent latex microbeads were injected iontophoretically or by pressure pulses (10 ms at 20 psi) into the taste-responsive regions of the NST and the ipsilateral PBN in six rats. Seven days later, the animals were euthanized and tissue sections containing the LH, CeA, BNST, and GC were processed for co-localization of FB and FG or GFB and RFB. The results showed that the CeA is the major source of input to the NST (82.3+/-7.6 cells/section) and the PBN (76.7+/-11.5), compared to the BNST (31.8+/-4.5; 37.0+/-4.8), the LH (35.0+/-5.4; 33.6+/-5.7), and the GC (27.5+/-4.0; 29.0+/-4.6). Of the total number of retrogradely labeled cells, the incidence of tracer co-localization was 17+/-3% in the GC, 17+/-2% in the CeA, 15+/-3% in the BNST and 16+/-1% in the LH. Thus, irrespective of forebrain source the majority of descending input to the gustatory NST and PBN originates from distinct neuronal populations. This arrangement provides an anatomical substrate for differential modulation of taste processing in the first and second central relays of the ascending gustatory system. PMID:19028464

  2. GPR30 is Positioned to Mediate Estrogen Effects on Basal Forebrain Cholinergic Neurons and Cognitive Performance

    PubMed Central

    Hammond, R.; Gibbs, R.B.

    2011-01-01

    Beneficial effects of estrogen therapy on cognitive performance diminish with age and time following the loss of ovarian function. This has led to the ‘Window of Opportunity’ hypothesis, which states that estrogen therapy must be administered within a limited period of time following menopause in order to be effective. Effects of estrogen therapy on cognitive performance are due, at least in part, to effects on cholinergic afferents innervating the hippocampus and cortex, and it has been suggested that the loss of estrogen effect with age and time following menopause is due to a substantial reduction in the function of these projections. The mechanisms that underlie the effects are not clear. GPR30 is a novel G-protein coupled estrogen receptor that is expressed in brain and other tissues. Our recent studies show that GPR30 is expressed in areas of the brain important for spatial learning, memory, and attention. In addition, GPR30 in expressed by the vast majority of cholinergic neurons in the basal forebrain, and appears to be an important regulator of basal forebrain cholinergic function. We hypothesize that GPR30 plays an important role in mediating direct effects of estradiol on basal forebrain cholinergic neurons, with corresponding effects on cognitive performance. Hence, GPR30 may be an important target for developing new therapies that can enhance or restore estrogen effects on cognitive performance in older women. Here we briefly review the cholinergic hypothesis and summarize our findings to date showing effects of a GPR30 agonist and antagonist on basal forebrain cholinergic function and cognitive performance. PMID:21138734

  3. Extracellular signal-regulated kinase phosphorylation in forebrain neurones contributes to osmoregulatory mechanisms

    PubMed Central

    Dine, Julien; Ducourneau, Vincent R R; Fénelon, Valérie S; Fossat, Pascal; Amadio, Aurélie; Eder, Matthias; Israel, Jean-Marc; Oliet, Stéphane H R; Voisin, Daniel L

    2014-01-01

    Vasopressin secretion from the magnocellular neurosecretory cells (MNCs) is crucial for body fluid homeostasis. Osmotic regulation of MNC activity involves the concerted modulation of intrinsic mechanosensitive ion channels, taurine release from local astrocytes as well as excitatory inputs derived from osmosensitive forebrain regions. Extracellular signal-regulated protein kinases (ERK) are mitogen-activated protein kinases that transduce extracellular stimuli into intracellular post-translational and transcriptional responses, leading to changes in intrinsic neuronal properties and synaptic function. Here, we investigated whether ERK activation (i.e. phosphorylation) plays a role in the functioning of forebrain osmoregulatory networks. We found that within 10 min after intraperitoneal injections of hypertonic saline (3 m, 6 m) in rats, many phosphoERK-immunopositive neurones were observed in osmosensitive forebrain regions, including the MNC containing supraoptic nuclei. The intensity of ERK labelling was dose-dependent. Reciprocally, slow intragastric infusions of water that lower osmolality reduced basal ERK phosphorylation. In the supraoptic nucleus, ERK phosphorylation predominated in vasopressin neurones vs. oxytocin neurones and was absent from astrocytes. Western blot experiments confirmed that phosphoERK expression in the supraoptic nucleus was dose dependent. Intracerebroventricular administration of the ERK phosphorylation inhibitor U 0126 before a hyperosmotic challenge reduced the number of both phosphoERK-immunopositive neurones and Fos expressing neurones in osmosensitive forebrain regions. Blockade of ERK phosphorylation also reduced hypertonically induced depolarization and an increase in firing of the supraoptic MNCs recorded in vitro. It finally reduced hypertonically induced vasopressin release in the bloodstream. Altogether, these findings identify ERK phosphorylation as a new element contributing to the osmoregulatory mechanisms of

  4. Inhibition of microRNA-181 reduces forebrain ischemia-induced neuronal loss

    PubMed Central

    Moon, Jeong-mi; Xu, Lijun; Giffard, Rona G

    2013-01-01

    MicroRNA (miRNA), miR-181a, is enriched in the brain, and inhibition of miR-181a reduced astrocyte death in vitro and infarct volume after stroke in vivo. This study investigated the role of miR-181a in neuronal injury in vitro and hippocampal neuronal loss in vivo after forebrain ischemia. miR-181a levels were altered by transfection with mimic or antagomir. N2a cells subjected to serum deprivation and oxidative stress showed less cell death when miR-181a was reduced and increased death when miR-181a increased; protection was associated with increased Bcl-2 protein. In contrast, transfected primary neurons did not show altered levels of cell death when miR-181a levels changed. Naive male rats and rats stereotactically infused with miR-181a antagomir or control were subjected to forebrain ischemia and cornus ammonis (CA)1 neuronal survival and protein levels were assessed. Forebrain ischemia increased miR-181a expression and decreased Bcl-2 protein in the hippocampal CA1 region. miR-181a antagomir reduced miR-181a levels, reduced CA1 neuronal loss, increased Bcl-2 protein, and significantly prevented the decrease of glutamate transporter 1. Thus, miR-181a antagomir reduced evidence of astrocyte dysfunction and increased CA1 neuronal survival. miR-181a inhibition is thus a potential target in the setting of forebrain or global cerebral ischemia as well as focal ischemia. PMID:24002437

  5. Heterogeneous patterns of oligodendroglial differentiation in the forebrain of the opossum Didelphis marsupialis.

    PubMed

    Barradas, P C; Gomes, S S; Cavalcante, L A

    1998-01-01

    The differentiation of oligodendrocytes in the forebrain of the opossum (Didelphis marsupialis) has been studied by the immunohistochemical identification of 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) and by the autoradiographic detection of the uptake of 3H-thymidine. CNPase is expressed early in oligodendroglia somata and fibre sheaths (myelin) in the forebrain and its persistence in the cell bodies is regionally heterogeneous, being ephemeral in cells within the optic pathway, supraoptic decussation, and posterior commissure, of intermediate duration in the mamillo-thalamic fascicle, and stria medullaris, and long-lasting in other diencephalic and in telencephalic tracts. In the cerebral cortex, most CNPase+ cells have small somata and multiple processes (types I and II). CNPase-expressing oligodendrocytes are also regionally heterogeneous in terms of proliferative capability, which could not be detected in forebrain tracts or diencephalon, but has appeared in a small proportion of cells in the neocortical white matter and in the fimbria. Our findings provide additional evidence in favour of the heterogeneity of oligodendrocytes. PMID:9530996

  6. Widespread expression of BDNF but not NT3 by target areas of basal forebrain cholinergic neurons

    SciTech Connect

    Phillips, H.S.; Hains, J.M.; Laramee, G.R.; Rosenthal, A.; Winslow, J.W. )

    1990-10-12

    Brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3) are homologs of the well-known neurotrophic factor nerve growth factor. The three members of this family display distinct patterns of target specificity. To examine the distribution in brain of messenger RNA for these molecules, in situ hybridization was performed. Cells hybridizing intensely to antisense BDNF probe were located throughout the major targets of the rat basal forebrain cholinergic system, that is, the hippocampus, amygdala, and neocortex. Strongly hybridizing cells were also observed in structures associated with the olfactory system. The distribution of NT3 mRNA in forebrain was much more limited. Within the hippocampus, labeled cells were restricted to CA2, the most medial portion of CA1, and the dentate gyrus. In human hippocampus, cells expressing BDNF and mRNA are distributed in a fashion similar to that observed in the rat. These findings point to both basal forebrain cholinergic cells and olfactory pathways as potential central targets for BDNF.

  7. Altered cholesterol biosynthesis causes precocious neurogenesis in the developing mouse forebrain.

    PubMed

    Driver, Ashley M; Kratz, Lisa E; Kelley, Richard I; Stottmann, Rolf W

    2016-07-01

    We previously reported a mutation in the cholesterol biosynthesis gene, hydroxysteroid (17-beta) dehydrogenase 7 (Hsd17b7(rudolph)), that results in striking embryonic forebrain dysgenesis. Here we describe abnormal patterns of neuroprogenitor proliferation in the mutant forebrain, namely, a decrease in mitotic cells within the ventricular zone (VZ) and an increase through the remainder of the cortex by E11.5. Further evidence suggests mutant cells undergo abnormal interkinetic nuclear migration (IKNM). Furthermore, intermediate progenitors are increased at the expense of apical progenitors by E12.5, and post-mitotic neurons are expanded by E14.5. In vitro primary neuron culture further supports our model of accelerated cortical differentiation in the mutant. Combined administration of a statin and dietary cholesterol in utero achieved partial reversal of multiple developmental abnormalities in the Hsd17b7(rudolph) embryo, including the forebrain. These results suggest that abnormally increased levels of specific cholesterol precursors in the Hsd17b7(rudolph) embryo cause cortical dysgenesis by altering patterns of neurogenesis. PMID:26921468

  8. Forebrain neuroanatomy of the neonatal and juvenile dolphin (T. truncatus and S. coeruloalba).

    PubMed

    Parolisi, Roberta; Peruffo, Antonella; Messina, Silvia; Panin, Mattia; Montelli, Stefano; Giurisato, Maristella; Cozzi, Bruno; Bonfanti, Luca

    2015-01-01

    Knowledge of dolphin functional neuroanatomy mostly derives from post-mortem studies and non-invasive approaches (i.e., magnetic resonance imaging), due to limitations in experimentation on cetaceans. As a consequence the availability of well-preserved tissues for histology is scarce, and detailed histological analyses are referred mainly to adults. Here we studied the neonatal/juvenile brain in two species of dolphins, the bottlenose dolphin (Tursiops truncatus) and the striped dolphin (Stenella coeruleoalba), with special reference to forebrain regions. We analyzed cell density in subcortical nuclei, white/gray matter ratio, and myelination in selected regions at different anterior-posterior levels of the whole dolphin brain at different ages, to better define forebrain neuroanatomy and the developmental stage of the dolphin brain around birth. The analyses were extended to the periventricular germinal layer and the cerebellum, whose delayed genesis of the granule cell layer is a hallmark of postnatal development in the mammalian nervous system. Our results establish an atlas of the young dolphin forebrain and, on the basis of occurrence/absence of delayed neurogenic layers, confirm the stage of advanced brain maturation in these animals with respect to most terrestrial mammals. PMID:26594155

  9. Forebrain neuroanatomy of the neonatal and juvenile dolphin (T. truncatus and S. coeruloalba)

    PubMed Central

    Parolisi, Roberta; Peruffo, Antonella; Messina, Silvia; Panin, Mattia; Montelli, Stefano; Giurisato, Maristella; Cozzi, Bruno; Bonfanti, Luca

    2015-01-01

    Knowledge of dolphin functional neuroanatomy mostly derives from post-mortem studies and non-invasive approaches (i.e., magnetic resonance imaging), due to limitations in experimentation on cetaceans. As a consequence the availability of well-preserved tissues for histology is scarce, and detailed histological analyses are referred mainly to adults. Here we studied the neonatal/juvenile brain in two species of dolphins, the bottlenose dolphin (Tursiops truncatus) and the striped dolphin (Stenella coeruleoalba), with special reference to forebrain regions. We analyzed cell density in subcortical nuclei, white/gray matter ratio, and myelination in selected regions at different anterior–posterior levels of the whole dolphin brain at different ages, to better define forebrain neuroanatomy and the developmental stage of the dolphin brain around birth. The analyses were extended to the periventricular germinal layer and the cerebellum, whose delayed genesis of the granule cell layer is a hallmark of postnatal development in the mammalian nervous system. Our results establish an atlas of the young dolphin forebrain and, on the basis of occurrence/absence of delayed neurogenic layers, confirm the stage of advanced brain maturation in these animals with respect to most terrestrial mammals. PMID:26594155

  10. The neuroprotective mechanism of ampicillin in a mouse model of transient forebrain ischemia

    PubMed Central

    Lee, Kyung-Eon; Cho, Kyung-Ok; Choi, Yun-Sik

    2016-01-01

    Ampicillin, a β-lactam antibiotic, dose-dependently protects neurons against ischemic brain injury. The present study was performed to investigate the neuroprotective mechanism of ampicillin in a mouse model of transient global forebrain ischemia. Male C57BL/6 mice were anesthetized with halothane and subjected to bilateral common carotid artery occlusion for 40 min. Before transient forebrain ischemia, ampicillin (200 mg/kg, intraperitoneally [i.p.]) or penicillin G (6,000 U/kg or 20,000 U/kg, i.p.) was administered daily for 5 days. The pretreatment with ampicillin but not with penicillin G signifi cantly attenuated neuronal damage in the hippocampal CA1 subfield. Mechanistically, the increased activity of matrix metalloproteinases (MMPs) following forebrain ischemia was also attenuated by ampicillin treatment. In addition, the ampicillin treatment reversed increased immunoreactivities to glial fibrillary acidic protein and isolectin B4, markers of astrocytes and microglia, respectively. Furthermore, the ampicillin treatment significantly increased the level of glutamate transporter-1, and dihydrokainic acid (DHK, 10 mg/kg, i.p.), an inhibitor of glutamate transporter-1 (GLT-1), reversed the neuroprotective effect of ampicillin. Taken together, these data indicate that ampicillin provides neuroprotection against ischemia-reperfusion brain injury, possibly through inducing the GLT-1 protein and inhibiting the activity of MMP in the mouse hippocampus. PMID:26937215