Michael Tsoory

The anxiolytic effect of environmental enrichment is mediated via amygdalar CRF receptor type 1

Environmental enrichment (EE) is known to have an anxiolytic effect in several animal models; however, the molecular mechanisms underlying these behavioral changes are not understood. In this study, we have shown that the anxiolytic effect of EE is associated with alterations in the corticotropin-releasing factor receptor type 1 (CRFR1) expression levels in the limbic system. We found that the decrease in anxiety-like behavior after housing in enriched conditions was associated with very low levels of CRFR1 mRNA expression in the basolateral amygdala of C57BL/6 mice. We further showed using a lentiviral-based system of RNA interference, that knockdown of CRFR1 mRNA expression in the basolateral amygdala induces a significant decrease in anxiety levels, similar to those achieved by EE nurture. Our data strongly suggest that reduced expression of CRFR1 mRNA levels in the basolateral amygdala mediates the effect of EE on anxiety-like behavior.

Prolonged and site-specific over-expression of corticotropin-releasing factor reveals differential roles for extended amygdala nuclei in emotional regulation

Corticotropin-releasing factor (CRF) has a key role in the central stress response, and altered levels of this neuropeptide are linked to stress-related psychopathologies such as anxiety and depression. These disorders are associated with the inability to properly regulate stress response, specifically following exposure to prolonged stressful stimuli. Therefore, the current study assessed the effects of prolonged and site-specific over-expression of CRF, which mimics the state of chronic production, in extended amygdala nuclei that are known to be involved in mediating anxiety-like states. We first constructed and generated lentiviruses that overexpress (OE) CRF in a robust and stable manner, and then generated two male mouse models continuously over-expressing CRF, either at the central nucleus of the amygdala (CeA), or at the dorsolateral subdivision of the bed nucleus of the stria terminalis (BNSTdl). After 4 months, behavioral assessments were conducted for anxiety and depressive indices on these mice. Surprisingly, prolonged CRF OE at the CeA attenuated stress-induced anxiety-like behaviors, whereas prolonged CRF OE in the BNSTdl increased depressive-like behaviors, without affecting anxiety levels. These results show possible differential roles for CRF expressed by distinct loci of the extended amygdala, in mediating stress-induced emotional behaviors.

A triple urocortin knockout mouse model reveals an essential role for urocortins in stress recovery

Responding to stressful events requires numerous adaptive actions involving integrated changes in the central nervous and neuroendocrine systems. Numerous studies have implicated dysregulation of stress-response mechanisms in the etiology of stress-induced psychopathophysiologies. The urocortin neuropeptides are members of the corticotropin-releasing factor family and are associated with the central stress response. In the current study, a triple-knockout (tKO) mouse model lacking all three urocortin genes was generated. Intriguingly, these urocortin tKO mice exhibit increased anxiety-like behaviors 24 h following stress exposure but not under unstressed conditions or immediately following exposure to acute stress. The inability of these mutants to recover properly from the exposure to an acute stress was associated with robust alterations in the expression profile of amygdalar genes and with dysregulated serotonergic function in stress-related neurocircuits. These findings position the urocortins as essential factors in the stress-recovery process and suggest the tKO mouse line as a useful stress-sensitive mouse model.

Susceptibility to PTSD-Like Behavior Is Mediated by Corticotropin-Releasing Factor Receptor Type 2 Levels in the Bed Nucleus of the Stria Terminalis

Posttraumatic stress disorder (PTSD) is a debilitating disease, which affects 8–10% of the population exposed to traumatic events. The factors that make certain individuals susceptible to PTSD and others resilient are currently unknown. Corticotropin-releasing factor receptor type 2 (CRFR2) has been implicated in mediating stress coping mechanisms. Here, we use a physiological PTSD-like animal model and an in-depth battery of tests that reflect the symptomology of PTSD to separate mice into subpopulations of “PTSD-like” and “Resilient” phenotypes. PTSD-like mice are hypervigilant, hyperalert, insomniac, have impaired attention and risk assessment, as well as accompanying attenuated corticosterone levels. Intriguingly, PTSD-like mice show long-term robust upregulation of BNST-CRFR2 mRNA levels, and BNST-CRFR2-specific lentiviral knockdown reduces susceptibility to PTSD-like behavior. Additionally, using a BNST mRNA expression array, PTSD-like mice exhibit a general transcriptional attenuation profile, which was associated with upregulation of the BNST-deacetylation enzyme, HDAC5. We suggest PTSD to be a disease of maladaptive coping.

Urocortin-1 and -2 double-deficient mice show robust anxiolytic phenotype and modified serotonergic activity in anxiety circuits

The urocortin (Ucn) family of neuropeptides is suggested to be involved in homeostatic coping mechanisms of the central stress response through the activation of corticotropin-releasing factor receptor type 2 (CRFR2). The neuropeptides, Ucn1 and Ucn2, serve as endogenous ligands for the CRFR2, which is highly expressed by the dorsal raphe serotonergic neurons and is suggested to be involved in regulating major component of the central stress response. Here, we describe genetically modified mice in which both Ucn1 and Ucn2 are developmentally deleted. The double knockout mice showed a robust anxiolytic phenotype and altered hypothalamic–pituitary–adrenal axis activity compared with wild-type mice. The significant reduction in anxiety-like behavior observed in these mice was further enhanced after exposure to acute stress, and was correlated with the levels of serotonin and 5-hydroxyindoleacetic acid measured in brain regions associated with anxiety circuits. Thus, we propose that the Ucn/CRFR2 serotonergic system has an important role in regulating homeostatic equilibrium under challenge conditions.

Post-Weaning to Pre-Pubertal (‘Juvenile’) Stress: A Model of Induced Predisposition to Stress-Related Disorders

Human studies suggest that childhood trauma predisposes individuals to develop stress-related disorders such as depression and post-traumatic stress disorder (PTSD). Recent years have witnessed growing interest in effectively modeling in animals the long-term effects of childhood emotional trauma on stress responses in adulthood. Most studies concerned with the impact of early-life stress on subsequent stress responses in adulthood in rodents have focused on the post-natal pre-weaning period. However, psychiatric studies often refer to human childhood rather than infancy when investigating the patients’ traumatic history of stress-related psychopathologies. In accordance with that, we have examined the consequences of stress exposure at a later early-life period, the post-weaning, pre-puberty (juvenile) period, which holds greater resemblance to human childhood. This review summarizes a series of studies examining the impact of exposure of rats to stressors during ‘juvenility’ (‘juvenile stress’) on the ability of these animals to cope with stress later in life. Exposure to relatively brief but significant stress experience during juvenility was found to impair the ability of animals to cope with stressful challenges in adulthood. These behavioral manifestations were associated with lasting alterations in limbic system brain regions of neuromodulatory pathways, such as alterations in the expression of cell adhesion molecules, GABAergic system functioning and alterations in levels of circulating corticosterone. Importantly, these studies have also demonstrated considerable individual and sex differences, which call for the development of adequate analysis approaches. The juvenile stress model combined with characterization of individual profiles is presented as a useful model to study in rodents different facets of stress-related disorders and neural mechanisms of vulnerability and resilience to stress.

Trisomy of the G protein-coupled K+ channel gene, Kcnj6, affects reward mechanisms, cognitive functions, and synaptic plasticity in mice

G protein-activated inwardly rectifying K+ channels (GIRK) generate slow inhibitory postsynaptic potentials in the brain via Gi/o protein-coupled receptors. GIRK2, a GIRK subunit, is widely abundant in the brain and has been implicated in various functions and pathologies, such as learning and memory, reward, motor coordination, and Down syndrome. Down syndrome, the most prevalent cause of mental retardation, results from the presence of an extra maternal chromosome 21 (trisomy 21), which comprises the Kcnj6 gene (GIRK2). The present study examined the behaviors and cellular physiology properties in mice harboring a single trisomy of the Kcnj6 gene. Kcnj6 triploid mice exhibit deficits in hippocampal-dependent learning and memory, altered responses to rewards, hampered depotentiation, a form of excitatory synaptic plasticity, and have accentuated long-term synaptic depression. Collectively the findings suggest that triplication of Kcnj6 gene may play an active role in some of the abnormal neurological phenotypes found in Down syndrome.

When two become one: The role of oxytocin in interpersonal coordination and cooperation

Cooperation involves intentional coordinated acts performed to achieve potentially positive outcomes. Here we present a novel explanatory model of cooperation, which focuses on the role of the oxytocinergic system in promoting interpersonal coordination and synchrony. Cooperation was assessed using a novel computerized drawing task that may be performed individually or cooperatively by two participants who coordinate their actions. Using a within-subject crossover design, 42 participants performed the task alone and with a partner following the administration of placebo and oxytocin 1 week apart. The data indicate that following placebo administration, participants performed better alone than in pairs. Yet, the administration of oxytocin improved paired performance up to the level of individual performance. This effect depended on the personality traits of cooperativeness or competitiveness. It is concluded that oxytocin may play a key role in enhancing social synchrony and coordination of behaviors required for cooperation.

Reduced ceramide synthase 2 activity causes progressive myoclonic epilepsy.

Ceramides are precursors of complex sphingolipids (SLs), which are important for normal functioning of both the developing and mature brain. Altered SL levels have been associated with many neurodegenerative disorders, including epilepsy, although few direct links have been identified between genes involved in SL metabolism and epilepsy.

Oligodendrogenesis and myelinogenesis during postnatal development effect of glatiramer acetate

Myelinogenesis in the mammal nervous system occurs predominantly postnatally. Glatiramer acetate (GA), a drug for the treatment for multiple sclerosis (MS), has been shown to induce immunomodulation and neuroprotection in the inflamed CNS in MS and in experimental autoimmune encephalomyelitis (EAE). Here we investigated whether GA can affect myelinogenesis and oligodendrogenesis in the developing nervous system under nonpathological conditions. Towards this end we studied myelination in mice injected daily by GA, at postnatal Days 7–21. Immunohistological and ultrastructural analyses revealed significant elevation in the number of myelinated axons as well as in the thickness of the myelin encircling them and their resulting g‐ratios, in spinal cords of GA‐injected mice compared with their PBS‐injected littermates, at postnatal Day 14. Elevation in myelinated axons was detected also in the peripheral ventral roots of the motor nerves. GA induced also an increase in axonal diameter, implying an effect on the overall development of the nervous system. A prominent elevation in the amount of progenitor oligodendrocytes and their BrdU incorporation, as well as in mature oligodendrocytes indicated that the effect of GA is linked to increased proliferation and differentiation along the oligodendroglial maturation cascade. In addition, elevation in insulin‐like growth factor (IGF‐1) and brain‐derived neurotrophic factor (BDNF) was found in the white matter of the GA‐injected mice. Furthermore, a functional advantage in rotating rod test was exhibited by GA‐injected mice over their littermates at postnatal Day 21. These cumulative findings corroborate the beneficial effect of GA on oligodendrogenesis and myelination. GLIA 2014;62:649–665