Gal Richter-levin - Academia.edu (original) (raw)

Papers by Gal Richter-levin

Research paper thumbnail of Distinct Neural Representations and Cognitive Behaviors Attributable to Naturally Developed Active Avoidance or Reactive Escape Strategies in the Male Rat

International Journal of Neuropsychopharmacology

Background The high individual variability in coping with stress is often attributed to genetic b... more Background The high individual variability in coping with stress is often attributed to genetic background differences, sustained environmental conditions, or a combination of both. However, the neural mechanisms underlying coping style variability are still poorly understood. Methods Here we examined the impact of a single extended emotional challenge on coping style variability and the associated involvement of the hippocampus, medial prefrontal cortex (mPFC), and periaqueductal gray (PAG). Male Sprague-Dawley rats (n = 170) were trained in an extended 2-way shuttle avoidance (eTWSA) task for 7 days, and daily avoidance rates were measured. Forced swim test, elevated plus maze, or Morris water maze was tested before or after eTWSA exposure. Excitotoxic lesion of the hippocampal dentate gyrus (DG) was performed by Ibotenic infusion. Transient pharmacological blocking of DG, mPFC, or PAG was performed by muscimol or CNQX+TTX infusion. Results Exposing rats to eTWSA was found to lead...

Research paper thumbnail of Developing of Focal Ischemia in the Hippocampus or the Amygdala Reveals a Regional Compensation Rule for Fear Memory Acquisition

eneuro

Circuit compensation is often observed in patients with acute ischemic stroke, suggesting the imp... more Circuit compensation is often observed in patients with acute ischemic stroke, suggesting the importance of the interaction between brain regions. Also, contextual fear memory is an association between multisensory contexts and fearful stimuli, for which the interaction between the hippocampus and the amygdala is believed to be critical. To understand how focal ischemia in one region could influence the other region, we used a modified photo-thrombosis to induce focal ischemia in the hippocampus or the amygdala or both in freely-moving rats. We found that the learning curve and short-term memory (STM) were not affected in the rats although focal ischemia was induced 5 h before learning in either the hippocampus or the amygdala; these were impaired by the induction of ischemia in both the regions. Furthermore, the learning curve and STM were impaired when ischemia was induced 24 h before learning in either the hippocampus or the amygdala when the synaptic transmission was altered in ...

Research paper thumbnail of Exposure to Juvenile Stress Induces Epigenetic Alterations in the GABAergic System in Rats

Genes

Epigenetics is a gene–environment interaction mechanism, manifested mostly through changes in reg... more Epigenetics is a gene–environment interaction mechanism, manifested mostly through changes in regulatory gene expression. Stress is an established environmental factor known to induce epigenetic changes. This study aimed to assess the long-term effect of stress as juveniles, or juvenile and adult stress, on alterations in glutamic acid decarboxylase genes (GAD65, GAD67). We assessed DNA methylation and RNA expression in four rat groups: (1) control group, (2) juvenile stress group sacrificed two days following stress exposure (JSe) (RNA only), (3) juvenile stress group sacrificed as adults (JS), and (4) juvenile and adult stress group (JS + AS). Three different areas of the brain were examined in each group: the dorsal dentate gyrus (dDG), the dorsal CA1 (dCA1), and the basolateral amygdala (BLA). A significantly low methylation level of GAD65 in the BLA was observed among the JS group, followed by almost complete recovery among the JS + AS group. However, in dDG, an opposite trend ...

Research paper thumbnail of Correction to: Sex-specific roles of hippocampal microRNAs in stress vulnerability and resilience

Translational Psychiatry

The original version of this article unfortunately contained a mistake in an author name. Rudulov... more The original version of this article unfortunately contained a mistake in an author name. Rudulovic, J. should be Radulovic, J. The original article has been corrected.

Research paper thumbnail of Individual behavioral profiling as a translational approach to assess treatment efficacy in an animal model of post-traumatic stress disorder

Frontiers in Neuroscience

A major challenge in treating post-traumatic stress disorder (PTSD) continues to be the large var... more A major challenge in treating post-traumatic stress disorder (PTSD) continues to be the large variability in responsiveness to pharmacotherapy. Only 20–30% of patients experience total remission to a specific treatment, while others demonstrate either partial remission or no response. However, this heterogeneity in response to pharmacotherapy has not been adequately addressed in animal models, since these analyze the averaged group effects, ignoring the individual variability to treatment response, which seriously compromises the translation power of such models. Here we examined the possibility of employing an “individual behavioral profiling” approach, originally developed to differentiate between “affected” and “exposed-unaffected” individuals in an animal model of PTSD, to also enable dissociating “responders” or “non-responders” after SSRI (fluoxetine) treatment. Importantly, this approach does not rely on a group averaged response to a single behavioral parameter, but consider...

Research paper thumbnail of Active resilience in response to traumatic stress

Stress Resilience

Abstract The mechanisms behind individual variability that lead only some individuals to develop ... more Abstract The mechanisms behind individual variability that lead only some individuals to develop stress-related psychopathologies are one of the key questions in stress research today. Here, we explore the contribution of one target molecule, the GABA synthetic enzyme glutamic acid decarboxylase (GAD) 65, to mechanisms of vulnerability and resilience. GAD65 is critically involved in the activity-dependent regulation of GABAergic inhibition in the central nervous system. It is also required for the maturation of the GABAergic system during adolescence, a period that is critical for the development of several neuropsychiatric diseases. Mice bearing a null mutation of the GAD65 gene develop hyperexcitability of the amygdala and hippocampus, and a phenotype of increased anxiety and pathological fear memory reminiscent of posttraumatic stress disorder. However, GAD65 haplodeficiency, which results in delayed postnatal increase of GABA levels, provides resilience to juvenile stress induced anxiety. Results obtained so far clearly indicate that GAD65 functioning is relevant to both stress vulnerability and stress resilience. The variable results regarding stress-related alterations in the expression of GAD65, together with the differences between effects of homozygous GAD65(−/−) knockout and GAD65 haplodeficiency, suggest that the role of GAD65 in stress vulnerability and resilience may differ in different brain regions and developmental stages. More temporal- and spatial-specific manipulations of expression are required to more accurately describe the role played by this enzyme in coping with stress. This is also important when examining the role of other target molecules in individual differences related to stress vulnerability and resilience.

Research paper thumbnail of Author response for "Intra-amygdala metaplasticity modulation of fear extinction learning

Research paper thumbnail of Network Neuromodulation of Opioid and GABAergic Receptors Following a Combination of “Juvenile” and “Adult Stress” in Rats

International Journal of Molecular Sciences, 2020

Early life stress is suggested to alter behavioral responses during stressful challenges in adult... more Early life stress is suggested to alter behavioral responses during stressful challenges in adulthood and to exacerbate pathological symptoms that reminisce posttraumatic stress disorder (PTSD). These effects are often associated with changes in γ-Aminobutyric acid type A (GABAA) and κ opioid receptor expression and neuromodulation of the limbic system. Anxiety-like and stress coping behaviors were assessed in rats exposed to stress in adulthood on the background of previous exposure to stress in juvenility. Two weeks following behavioral assessment in adulthood, GABAAR α1 and α2 subunits and κ opioid receptor expression levels were measured in the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), amygdala, and periaqueductal gray (PAG). To illustrate changes at the network level, an integrated expression profile was constructed. We found that exposure to juvenile stress affected rats’ behavior during adult stress. The combination of juvenile and adult stress significantly a...

Research paper thumbnail of Compartmentalised perturbation of GABAergic synapses in the basolateral amygdala principal neurons

European Neuropsychopharmacology, 2017

Research paper thumbnail of Pten is a key intrinsic factor regulating raphe 5-HT neuronal plasticity and depressive behaviors in mice

Translational Psychiatry, 2021

Serotonin (5-HT)-based antidepressants, selective serotonin reuptake inhibitors (SSRIs) aim to en... more Serotonin (5-HT)-based antidepressants, selective serotonin reuptake inhibitors (SSRIs) aim to enhance serotonergic activity by blocking its reuptake. We propose PTEN as a target for an alternative approach for regulating 5-HT neuron activity in the brain and depressive behaviors. We show that PTEN is elevated in central 5-HT neurons in the raphe nucleus by chronic stress in mice, and selective deletion of Pten in the 5-HT neurons induces its structural plasticity shown by increases of dendritic branching and density of PSD95-positive puncta in the dendrites. 5-HT levels are elevated and electrical stimulation of raphe neurons evokes more 5-HT release in the brain of condition knockout (cKO) mice with Pten-deficient 5-HT neurons. In addition, the 5-HT neurons remain normal electrophysiological properties but have increased excitatory synaptic inputs. Single-cell RNA sequencing revealed gene transcript alterations that may underlay morphological and functional changes in Pten-deficie...

Research paper thumbnail of A Translational Paradigm to Study the Effects of Uncontrollable Stress in Humans

International Journal of Molecular Sciences, 2020

Theories on the aetiology of depression in humans are intimately linked to animal research on str... more Theories on the aetiology of depression in humans are intimately linked to animal research on stressor controllability effects. However, explicit translations of established animal designs are lacking. In two consecutive studies, we developed a translational paradigm to study stressor controllability effects in humans. In the first study, we compared three groups of participants, one exposed to escapable stress, one yoked inescapable stress group, and a control group not exposed to stress. Although group differences indicated successful stress induction, the manipulation failed to differentiate groups according to controllability. In the second study, we employed an improved paradigm and contrasted only an escapable stress group to a yoked inescapable stress group. The final design successfully induced differential effects on self-reported perceived control, exhaustion, helplessness, and behavioural indices of adaptation to stress. The latter were examined in a new escape behaviour ...

Research paper thumbnail of The effects of serotonin depletion and raphe grafts on hippocampal electrophysiology and behavior

The Journal of Neuroscience, 1991

The involvement of the serotonergic system in spatial learning and a possible correlation between... more The involvement of the serotonergic system in spatial learning and a possible correlation between serotonergic modulation of hippocampal electrical activity and spatial learning were studied in rats. Control, partial septal-lesioned (SL), 5,7-dihydroxytryptamine (5,7-DHT)- injected (DHT), double-lesioned (5,7-DHT and SL; DL), and DL rats that were transplanted with embryonic raphe grafts into the hippocampus (RG) were tested in a spatial task in a water maze and in an active avoidance shuttle-box task. The responses of the dentate gyrus (DG) to perforant-path (PP) stimulation were examined in the same rats, under the following conditions: (1) priming stimulation of the PP (testing feedback inhibition), (2) priming stimulation of the commissural pathway (testing feedforward inhibition), (3) during repeated stimulation of the PP at 7 Hz (frequency potentiation), and (4) following tetanic stimulation [long-term potentiation (LTP)]. DL, but not DHT or SL, treatment severely impaired the...

Research paper thumbnail of Exposure to prolonged controllable or uncontrollable stress affects GABAergic function in sub-regions of the hippocampus and the amygdala

Neurobiology of Learning and Memory, 2017

The degree of behavioral control that an individual has over a stressor can critically determine ... more The degree of behavioral control that an individual has over a stressor can critically determine its behavioral and neurochemical outcomes. Exposure to uncontrollable stress was previously shown to have detrimental effects on behavior, whereas exposure to equivalent controllable stress prevented these negative outcomes and even improved later stress coping. As many lines of evidence show, stress exposure can have maladaptive changes on inhibitory circuitry, and these effects were largely shown in the hippocampus and amygdala. In the current study we set out to examine alterations in GABAergic activity following exposure to the prolonged two way shuttle (TWS) avoidance task, focusing on the GABA-related factors glutamate decarboxylase (GAD)65, Cholecystokinin (CCK) and neuropeptide Y (NPY). As recent views of the hippocampus assume regional specificity in hippocampal function, we examined different regions in the hippocampus, as well as the basolateral amygdala (BLA). Our findings reveal similar alterations in GAD65 in BLA for both controllable and uncontrollable stress exposure, but differential alterations in GAD65 and NPY in the dorsal dentate gyrus (DG). Synaptic plasticity and inhibitory activity in the dorsal DG was further assessed by applying different stimulation protocols and measuring evoked field potentials in vivo. Our results support a role for the DG in stress processing, emphasizing its sensitivity to the nature of the stressor. Key word: stress controllability; GABA; neuropeptide Y; glutamate decarboxylase (GAD)65; cholecystokinin; hippocampus; dentate gyrus; basolateral amygdala; long term potentiation Abbreviations: TWStwo way shuttle dDGdorsal dentate gyrus vDGventral dentate gyrus dCA1dorsal CA1 vCA1ventral CA1

Research paper thumbnail of PTSD modeling in rodents shows alternating patterns of limbic activity in various types of reactions to stress

Molecular Psychiatry, 2016

Dual-colored immunohistochemical labeling for c-Fos expression (magenta) as a marker of neural ac... more Dual-colored immunohistochemical labeling for c-Fos expression (magenta) as a marker of neural activation and for GAD67 (green) as a marker of inhibitory GABAergic cells in the rat BLA. White arrows point to dual-labeled cells, co-expressing GAD67 and c-Fos, indicating activated inhibitory interneurons. For more information on this topic, please refer to the article by Ritov et al. on pages 630-641.

Research paper thumbnail of Corrigendum: Light exposure before learning improves memory consolidation at night

Scientific reports, Jan 20, 2016

The original version of this Article contained a typographical error in the spelling of the autho... more The original version of this Article contained a typographical error in the spelling of the author Gal Richter-Levin, which was incorrectly given as Gal Richter-Levine. This has now been corrected in both the PDF and HTML versions of the Article.

Research paper thumbnail of Effects of novel vs. repeated mild stressful experiences on LTP induced simultaneously in the amygdala and hippocampus in freely behaving rats

Annals of the New York Academy of Sciences the Amygdala in Brain Function Basic and Clinical Approaches, 2003

Research paper thumbnail of The Contribution of the Serotonergic Innervation of the Hippocampus to the Effects of Combined Cholinergic/Serotonergic Deficits

Neurotransmitter Interactions and Cognitive Function, 1992

A most disturbing aspect of aging is the reduction in cognitive abilities (Bartus et al., 1982; W... more A most disturbing aspect of aging is the reduction in cognitive abilities (Bartus et al., 1982; Weingartner et al., 1987). Although acetylcholine (ACh) is suggested to have a prime role in memory processes (Bartus et al., 1982; Kesner, 1988; Lebrun et al., 1990; Toumane et al., 1988), it is now widely accepted that other neuromodulatory systems participate, probably interactively, in these processes (Baker and Reynolds, 1989; Decker and McGaugh, 1991; Rossor and Iversen, 1986; Segal, 1982) and that a reduction in the functioning of these systems may underlie some aspects of memory deficits associated with aging (Allain et al., 1989; Steinbusch et al., 1989).

Research paper thumbnail of Local circuit activity and plasticity in the hippocampus – Potential relevance to emotional and traumatic memories

Frontiers in Behavioral Neuroscience, 2009

Research paper thumbnail of Actions of norepinephrine in the rat hippocampus

Progress in Brain Research, 1991

Acting at postsynaptic alpha 1- and beta 1-receptors, norepinephrine (NE) exerts a complex action... more Acting at postsynaptic alpha 1- and beta 1-receptors, norepinephrine (NE) exerts a complex action in rat hippocampus. It is currently believed that beta 1-receptor activation enhances excitability of recorded neurons, whereas alpha 1 activation suppresses reactivity to afferent stimulation. These reported effects of alpha-agonists are not consistent with alpha 1 effects found elsewhere in the brain. We have conducted experiments in the anesthetized rat and found that an amphetamine-induced increase in the dentate gyrus population spike can be blocked by a beta-antagonist but also by an alpha 1-antagonist. We have conducted experiments in the brain slide preparation and found that an alpha-agonist, phenylephrine (PHE), selectively enhances responses to N-methyl-D-aspartate (NMDA) but not to quisqualate. We propose that the product of activation of both alpha- and beta-receptor types will enhance reactivity of hippocampal cells to afferent stimulation.

Research paper thumbnail of Unpredictable chronic stress in juvenile or adult rats has opposite effects, respectively, promoting and impairing resilience

Stress (Amsterdam, Netherlands), 2012

We evaluated the effects of early maternal deprivation (MD; age 7-14 days) alone or in combinatio... more We evaluated the effects of early maternal deprivation (MD; age 7-14 days) alone or in combination with unpredictable chronic stress (UCS; MDUN; 28-84 days) on anxiety and learning in 90 days old adult rats. We hypothesized that exposure to both stressors (MDUN) would be more detrimental than exposure to one or neither. Unexpectedly, adult rats from the MDUN group did not differ from control animals, whereas adult MD animals exhibited impaired avoidance learning. We next investigated the effect of juvenile-onset (30-90 days) versus adult-onset (60-90 days) stress on avoidance learning in adulthood (90 days). We found that adult-onset chronic stress impaired avoidance learning and memory whereas juvenile-onset stress did not. Thus, the results again indicate that juvenile exposure to UCS induces resilience rather than impairment.

Research paper thumbnail of Distinct Neural Representations and Cognitive Behaviors Attributable to Naturally Developed Active Avoidance or Reactive Escape Strategies in the Male Rat

International Journal of Neuropsychopharmacology

Background The high individual variability in coping with stress is often attributed to genetic b... more Background The high individual variability in coping with stress is often attributed to genetic background differences, sustained environmental conditions, or a combination of both. However, the neural mechanisms underlying coping style variability are still poorly understood. Methods Here we examined the impact of a single extended emotional challenge on coping style variability and the associated involvement of the hippocampus, medial prefrontal cortex (mPFC), and periaqueductal gray (PAG). Male Sprague-Dawley rats (n = 170) were trained in an extended 2-way shuttle avoidance (eTWSA) task for 7 days, and daily avoidance rates were measured. Forced swim test, elevated plus maze, or Morris water maze was tested before or after eTWSA exposure. Excitotoxic lesion of the hippocampal dentate gyrus (DG) was performed by Ibotenic infusion. Transient pharmacological blocking of DG, mPFC, or PAG was performed by muscimol or CNQX+TTX infusion. Results Exposing rats to eTWSA was found to lead...

Research paper thumbnail of Developing of Focal Ischemia in the Hippocampus or the Amygdala Reveals a Regional Compensation Rule for Fear Memory Acquisition

eneuro

Circuit compensation is often observed in patients with acute ischemic stroke, suggesting the imp... more Circuit compensation is often observed in patients with acute ischemic stroke, suggesting the importance of the interaction between brain regions. Also, contextual fear memory is an association between multisensory contexts and fearful stimuli, for which the interaction between the hippocampus and the amygdala is believed to be critical. To understand how focal ischemia in one region could influence the other region, we used a modified photo-thrombosis to induce focal ischemia in the hippocampus or the amygdala or both in freely-moving rats. We found that the learning curve and short-term memory (STM) were not affected in the rats although focal ischemia was induced 5 h before learning in either the hippocampus or the amygdala; these were impaired by the induction of ischemia in both the regions. Furthermore, the learning curve and STM were impaired when ischemia was induced 24 h before learning in either the hippocampus or the amygdala when the synaptic transmission was altered in ...

Research paper thumbnail of Exposure to Juvenile Stress Induces Epigenetic Alterations in the GABAergic System in Rats

Genes

Epigenetics is a gene–environment interaction mechanism, manifested mostly through changes in reg... more Epigenetics is a gene–environment interaction mechanism, manifested mostly through changes in regulatory gene expression. Stress is an established environmental factor known to induce epigenetic changes. This study aimed to assess the long-term effect of stress as juveniles, or juvenile and adult stress, on alterations in glutamic acid decarboxylase genes (GAD65, GAD67). We assessed DNA methylation and RNA expression in four rat groups: (1) control group, (2) juvenile stress group sacrificed two days following stress exposure (JSe) (RNA only), (3) juvenile stress group sacrificed as adults (JS), and (4) juvenile and adult stress group (JS + AS). Three different areas of the brain were examined in each group: the dorsal dentate gyrus (dDG), the dorsal CA1 (dCA1), and the basolateral amygdala (BLA). A significantly low methylation level of GAD65 in the BLA was observed among the JS group, followed by almost complete recovery among the JS + AS group. However, in dDG, an opposite trend ...

Research paper thumbnail of Correction to: Sex-specific roles of hippocampal microRNAs in stress vulnerability and resilience

Translational Psychiatry

The original version of this article unfortunately contained a mistake in an author name. Rudulov... more The original version of this article unfortunately contained a mistake in an author name. Rudulovic, J. should be Radulovic, J. The original article has been corrected.

Research paper thumbnail of Individual behavioral profiling as a translational approach to assess treatment efficacy in an animal model of post-traumatic stress disorder

Frontiers in Neuroscience

A major challenge in treating post-traumatic stress disorder (PTSD) continues to be the large var... more A major challenge in treating post-traumatic stress disorder (PTSD) continues to be the large variability in responsiveness to pharmacotherapy. Only 20–30% of patients experience total remission to a specific treatment, while others demonstrate either partial remission or no response. However, this heterogeneity in response to pharmacotherapy has not been adequately addressed in animal models, since these analyze the averaged group effects, ignoring the individual variability to treatment response, which seriously compromises the translation power of such models. Here we examined the possibility of employing an “individual behavioral profiling” approach, originally developed to differentiate between “affected” and “exposed-unaffected” individuals in an animal model of PTSD, to also enable dissociating “responders” or “non-responders” after SSRI (fluoxetine) treatment. Importantly, this approach does not rely on a group averaged response to a single behavioral parameter, but consider...

Research paper thumbnail of Active resilience in response to traumatic stress

Stress Resilience

Abstract The mechanisms behind individual variability that lead only some individuals to develop ... more Abstract The mechanisms behind individual variability that lead only some individuals to develop stress-related psychopathologies are one of the key questions in stress research today. Here, we explore the contribution of one target molecule, the GABA synthetic enzyme glutamic acid decarboxylase (GAD) 65, to mechanisms of vulnerability and resilience. GAD65 is critically involved in the activity-dependent regulation of GABAergic inhibition in the central nervous system. It is also required for the maturation of the GABAergic system during adolescence, a period that is critical for the development of several neuropsychiatric diseases. Mice bearing a null mutation of the GAD65 gene develop hyperexcitability of the amygdala and hippocampus, and a phenotype of increased anxiety and pathological fear memory reminiscent of posttraumatic stress disorder. However, GAD65 haplodeficiency, which results in delayed postnatal increase of GABA levels, provides resilience to juvenile stress induced anxiety. Results obtained so far clearly indicate that GAD65 functioning is relevant to both stress vulnerability and stress resilience. The variable results regarding stress-related alterations in the expression of GAD65, together with the differences between effects of homozygous GAD65(−/−) knockout and GAD65 haplodeficiency, suggest that the role of GAD65 in stress vulnerability and resilience may differ in different brain regions and developmental stages. More temporal- and spatial-specific manipulations of expression are required to more accurately describe the role played by this enzyme in coping with stress. This is also important when examining the role of other target molecules in individual differences related to stress vulnerability and resilience.

Research paper thumbnail of Author response for "Intra-amygdala metaplasticity modulation of fear extinction learning

Research paper thumbnail of Network Neuromodulation of Opioid and GABAergic Receptors Following a Combination of “Juvenile” and “Adult Stress” in Rats

International Journal of Molecular Sciences, 2020

Early life stress is suggested to alter behavioral responses during stressful challenges in adult... more Early life stress is suggested to alter behavioral responses during stressful challenges in adulthood and to exacerbate pathological symptoms that reminisce posttraumatic stress disorder (PTSD). These effects are often associated with changes in γ-Aminobutyric acid type A (GABAA) and κ opioid receptor expression and neuromodulation of the limbic system. Anxiety-like and stress coping behaviors were assessed in rats exposed to stress in adulthood on the background of previous exposure to stress in juvenility. Two weeks following behavioral assessment in adulthood, GABAAR α1 and α2 subunits and κ opioid receptor expression levels were measured in the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), amygdala, and periaqueductal gray (PAG). To illustrate changes at the network level, an integrated expression profile was constructed. We found that exposure to juvenile stress affected rats’ behavior during adult stress. The combination of juvenile and adult stress significantly a...

Research paper thumbnail of Compartmentalised perturbation of GABAergic synapses in the basolateral amygdala principal neurons

European Neuropsychopharmacology, 2017

Research paper thumbnail of Pten is a key intrinsic factor regulating raphe 5-HT neuronal plasticity and depressive behaviors in mice

Translational Psychiatry, 2021

Serotonin (5-HT)-based antidepressants, selective serotonin reuptake inhibitors (SSRIs) aim to en... more Serotonin (5-HT)-based antidepressants, selective serotonin reuptake inhibitors (SSRIs) aim to enhance serotonergic activity by blocking its reuptake. We propose PTEN as a target for an alternative approach for regulating 5-HT neuron activity in the brain and depressive behaviors. We show that PTEN is elevated in central 5-HT neurons in the raphe nucleus by chronic stress in mice, and selective deletion of Pten in the 5-HT neurons induces its structural plasticity shown by increases of dendritic branching and density of PSD95-positive puncta in the dendrites. 5-HT levels are elevated and electrical stimulation of raphe neurons evokes more 5-HT release in the brain of condition knockout (cKO) mice with Pten-deficient 5-HT neurons. In addition, the 5-HT neurons remain normal electrophysiological properties but have increased excitatory synaptic inputs. Single-cell RNA sequencing revealed gene transcript alterations that may underlay morphological and functional changes in Pten-deficie...

Research paper thumbnail of A Translational Paradigm to Study the Effects of Uncontrollable Stress in Humans

International Journal of Molecular Sciences, 2020

Theories on the aetiology of depression in humans are intimately linked to animal research on str... more Theories on the aetiology of depression in humans are intimately linked to animal research on stressor controllability effects. However, explicit translations of established animal designs are lacking. In two consecutive studies, we developed a translational paradigm to study stressor controllability effects in humans. In the first study, we compared three groups of participants, one exposed to escapable stress, one yoked inescapable stress group, and a control group not exposed to stress. Although group differences indicated successful stress induction, the manipulation failed to differentiate groups according to controllability. In the second study, we employed an improved paradigm and contrasted only an escapable stress group to a yoked inescapable stress group. The final design successfully induced differential effects on self-reported perceived control, exhaustion, helplessness, and behavioural indices of adaptation to stress. The latter were examined in a new escape behaviour ...

Research paper thumbnail of The effects of serotonin depletion and raphe grafts on hippocampal electrophysiology and behavior

The Journal of Neuroscience, 1991

The involvement of the serotonergic system in spatial learning and a possible correlation between... more The involvement of the serotonergic system in spatial learning and a possible correlation between serotonergic modulation of hippocampal electrical activity and spatial learning were studied in rats. Control, partial septal-lesioned (SL), 5,7-dihydroxytryptamine (5,7-DHT)- injected (DHT), double-lesioned (5,7-DHT and SL; DL), and DL rats that were transplanted with embryonic raphe grafts into the hippocampus (RG) were tested in a spatial task in a water maze and in an active avoidance shuttle-box task. The responses of the dentate gyrus (DG) to perforant-path (PP) stimulation were examined in the same rats, under the following conditions: (1) priming stimulation of the PP (testing feedback inhibition), (2) priming stimulation of the commissural pathway (testing feedforward inhibition), (3) during repeated stimulation of the PP at 7 Hz (frequency potentiation), and (4) following tetanic stimulation [long-term potentiation (LTP)]. DL, but not DHT or SL, treatment severely impaired the...

Research paper thumbnail of Exposure to prolonged controllable or uncontrollable stress affects GABAergic function in sub-regions of the hippocampus and the amygdala

Neurobiology of Learning and Memory, 2017

The degree of behavioral control that an individual has over a stressor can critically determine ... more The degree of behavioral control that an individual has over a stressor can critically determine its behavioral and neurochemical outcomes. Exposure to uncontrollable stress was previously shown to have detrimental effects on behavior, whereas exposure to equivalent controllable stress prevented these negative outcomes and even improved later stress coping. As many lines of evidence show, stress exposure can have maladaptive changes on inhibitory circuitry, and these effects were largely shown in the hippocampus and amygdala. In the current study we set out to examine alterations in GABAergic activity following exposure to the prolonged two way shuttle (TWS) avoidance task, focusing on the GABA-related factors glutamate decarboxylase (GAD)65, Cholecystokinin (CCK) and neuropeptide Y (NPY). As recent views of the hippocampus assume regional specificity in hippocampal function, we examined different regions in the hippocampus, as well as the basolateral amygdala (BLA). Our findings reveal similar alterations in GAD65 in BLA for both controllable and uncontrollable stress exposure, but differential alterations in GAD65 and NPY in the dorsal dentate gyrus (DG). Synaptic plasticity and inhibitory activity in the dorsal DG was further assessed by applying different stimulation protocols and measuring evoked field potentials in vivo. Our results support a role for the DG in stress processing, emphasizing its sensitivity to the nature of the stressor. Key word: stress controllability; GABA; neuropeptide Y; glutamate decarboxylase (GAD)65; cholecystokinin; hippocampus; dentate gyrus; basolateral amygdala; long term potentiation Abbreviations: TWStwo way shuttle dDGdorsal dentate gyrus vDGventral dentate gyrus dCA1dorsal CA1 vCA1ventral CA1

Research paper thumbnail of PTSD modeling in rodents shows alternating patterns of limbic activity in various types of reactions to stress

Molecular Psychiatry, 2016

Dual-colored immunohistochemical labeling for c-Fos expression (magenta) as a marker of neural ac... more Dual-colored immunohistochemical labeling for c-Fos expression (magenta) as a marker of neural activation and for GAD67 (green) as a marker of inhibitory GABAergic cells in the rat BLA. White arrows point to dual-labeled cells, co-expressing GAD67 and c-Fos, indicating activated inhibitory interneurons. For more information on this topic, please refer to the article by Ritov et al. on pages 630-641.

Research paper thumbnail of Corrigendum: Light exposure before learning improves memory consolidation at night

Scientific reports, Jan 20, 2016

The original version of this Article contained a typographical error in the spelling of the autho... more The original version of this Article contained a typographical error in the spelling of the author Gal Richter-Levin, which was incorrectly given as Gal Richter-Levine. This has now been corrected in both the PDF and HTML versions of the Article.

Research paper thumbnail of Effects of novel vs. repeated mild stressful experiences on LTP induced simultaneously in the amygdala and hippocampus in freely behaving rats

Annals of the New York Academy of Sciences the Amygdala in Brain Function Basic and Clinical Approaches, 2003

Research paper thumbnail of The Contribution of the Serotonergic Innervation of the Hippocampus to the Effects of Combined Cholinergic/Serotonergic Deficits

Neurotransmitter Interactions and Cognitive Function, 1992

A most disturbing aspect of aging is the reduction in cognitive abilities (Bartus et al., 1982; W... more A most disturbing aspect of aging is the reduction in cognitive abilities (Bartus et al., 1982; Weingartner et al., 1987). Although acetylcholine (ACh) is suggested to have a prime role in memory processes (Bartus et al., 1982; Kesner, 1988; Lebrun et al., 1990; Toumane et al., 1988), it is now widely accepted that other neuromodulatory systems participate, probably interactively, in these processes (Baker and Reynolds, 1989; Decker and McGaugh, 1991; Rossor and Iversen, 1986; Segal, 1982) and that a reduction in the functioning of these systems may underlie some aspects of memory deficits associated with aging (Allain et al., 1989; Steinbusch et al., 1989).

Research paper thumbnail of Local circuit activity and plasticity in the hippocampus – Potential relevance to emotional and traumatic memories

Frontiers in Behavioral Neuroscience, 2009

Research paper thumbnail of Actions of norepinephrine in the rat hippocampus

Progress in Brain Research, 1991

Acting at postsynaptic alpha 1- and beta 1-receptors, norepinephrine (NE) exerts a complex action... more Acting at postsynaptic alpha 1- and beta 1-receptors, norepinephrine (NE) exerts a complex action in rat hippocampus. It is currently believed that beta 1-receptor activation enhances excitability of recorded neurons, whereas alpha 1 activation suppresses reactivity to afferent stimulation. These reported effects of alpha-agonists are not consistent with alpha 1 effects found elsewhere in the brain. We have conducted experiments in the anesthetized rat and found that an amphetamine-induced increase in the dentate gyrus population spike can be blocked by a beta-antagonist but also by an alpha 1-antagonist. We have conducted experiments in the brain slide preparation and found that an alpha-agonist, phenylephrine (PHE), selectively enhances responses to N-methyl-D-aspartate (NMDA) but not to quisqualate. We propose that the product of activation of both alpha- and beta-receptor types will enhance reactivity of hippocampal cells to afferent stimulation.

Research paper thumbnail of Unpredictable chronic stress in juvenile or adult rats has opposite effects, respectively, promoting and impairing resilience

Stress (Amsterdam, Netherlands), 2012

We evaluated the effects of early maternal deprivation (MD; age 7-14 days) alone or in combinatio... more We evaluated the effects of early maternal deprivation (MD; age 7-14 days) alone or in combination with unpredictable chronic stress (UCS; MDUN; 28-84 days) on anxiety and learning in 90 days old adult rats. We hypothesized that exposure to both stressors (MDUN) would be more detrimental than exposure to one or neither. Unexpectedly, adult rats from the MDUN group did not differ from control animals, whereas adult MD animals exhibited impaired avoidance learning. We next investigated the effect of juvenile-onset (30-90 days) versus adult-onset (60-90 days) stress on avoidance learning in adulthood (90 days). We found that adult-onset chronic stress impaired avoidance learning and memory whereas juvenile-onset stress did not. Thus, the results again indicate that juvenile exposure to UCS induces resilience rather than impairment.