Male and female mice are similarly susceptible to chronic nondiscriminatory social defeat stress despite differences in attack frequency from aggressor.

Rationale: Chronic stress is a major precipitating factor for mood disorders, which are diagnosed twice as frequently in women as in men. However, most preclinical models of chronic social defeat stress have limited use in females due to reduced aggression toward female intruders. The chronic non-discriminatory social defeat stress (CNSDS) model addresses these limitations by enabling the study of stress susceptibility across sexes in a variety of behavioral tasks including avoidance and simple reward behaviors.

Male and Female Mice Are Similarly Susceptible to Chronic Nondiscriminatory Social Defeat Stress Despite Differences in Attack Frequency from Aggressor.

Rationale: Mood disorders are often precipitated by chronic stress and can result in an inability to adapt to the environment and increased vulnerability to challenging experiences. While diagnoses of mood disorders are diagnosed twice as frequently in women than in men, most preclinical chronic social defeat stress mouse models exclude females due to decreased aggression toward female intruders.

Objectives: We previously reported that the chronic non-discriminatory social defeat stress (CNSDS) paradigm is effective in both sexes, allowing for comparisons between male and female mice.

Chemogenetic activation of corticotropin-releasing factor-expressing neurons in the anterior bed nucleus of the stria terminalis reduces effortful motivation behaviors.

Corticotropin-releasing factor (CRF) in the anterior bed nucleus of the stria terminalis (aBNST) is associated with chronic stress and avoidance behavior. However, CRF + BNST neurons project to reward- and motivation-related brain regions, suggesting a potential role in motivated behavior. We used chemogenetics to selectively activate CRF+ aBNST neurons in male and female CRF-ires-Cre mice during an effort-related choice task and a concurrent choice task.

Functional anatomy of the bed nucleus of the stria terminalis-hypothalamus neural circuitry: Implications for valence surveillance, addiction, feeding, and social behaviors.

The bed nucleus of the stria terminalis (BNST) is a medial basal forebrain structure that modulates the hypothalamo-pituitary-adrenal (HPA) axis. The heterogeneous subnuclei of the BNST integrate inputs from mood and reward-related areas and send direct inhibitory projections to the hypothalamus. The connections between the BNST and hypothalamus are conserved across species, promote activation of the HPA axis, and can increase avoidance of aversive environments, which is historically associated with anxiety behaviors.

Chronic non-discriminatory social defeat stress reduces effort-related motivated behaviors in male and female mice.

Reward and motivation deficits are prominent symptoms in many mood disorders, including depression. Similar reward and effort-related choice behavioral tasks can be used to study aspects of motivation in both rodents and humans. Chronic stress can precipitate mood disorders in humans and maladaptive reward and motivation behaviors in male rodents.

Dentate gyrus activin signaling mediates the antidepressant response.

Antidepressants that target monoaminergic systems, such as selective serotonin reuptake inhibitors (SSRIs), are widely used to treat neuropsychiatric disorders including major depressive disorder, several anxiety disorders, and obsessive-compulsive disorder. However, these treatments are not ideal because only a subset of patients achieve remission. The reasons why some individuals remit to antidepressant treatments while others do not are unknown.

Chronic corticosterone shifts effort-related choice behavior in male mice.

Rationale: Effort-related choice tasks are used to study aspects of motivation in both rodents and humans (Der-Avakian and Pizzagalli Biol Psychiatry 83(11):932-939, 2018). Various dopaminergic manipulations and antidepressant treatments can shift responding to these tasks (Randall et al. Int J Neuropsychopharmacol 18(2), 2014; Yohn et al.

Fluoxetine effects on behavior and adult hippocampal neurogenesis in female C57BL/6J mice across the estrous cycle.

Rationale: Some mood disorders, such as major depressive disorder, are more prevalent in women than in men. However, historically preclinical studies in rodents have a lower inclusion rate of females than males, possibly due to the fact that behavior can be affected by the estrous cycle. Several studies have demonstrated that chronic antidepressant treatment can decrease anxiety-associated behaviors and increase adult hippocampal neurogenesis in male rodents.

Chronic non-discriminatory social defeat is an effective chronic stress paradigm for both male and female mice.

Stress-related mood disorders are more prevalent in females than males, yet preclinical chronic stress paradigms were developed in male rodents and are less effective in female rodents. Here we characterize a novel chronic non-discriminatory social defeat stress (CNSDS) paradigm that results in comparable stress effects in both sexes. Male and female C57BL/6J mice were simultaneously introduced into the home cage of resident CD-1 aggressors for 10 daily 5-min sessions.

The role of 5-HT receptors in depression.

Depression is a polygenic and highly complex psychiatric disorder that remains a major burden on society. Antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), are some of the most commonly prescribed drugs worldwide. In this review, we will discuss the evidence that links serotonin and serotonin receptors to the etiology of depression and the mechanisms underlying response to antidepressant treatment.

The Behavioral Effects of the Antidepressant Tianeptine Require the Mu-Opioid Receptor.

Depression is a debilitating chronic illness that affects around 350 million people worldwide. Current treatments, such as selective serotonin reuptake inhibitors, are not ideal because only a fraction of patients achieve remission. Tianeptine is an effective antidepressant with a previously unknown mechanism of action.

Serotonin 1A and Serotonin 4 Receptors: Essential Mediators of the Neurogenic and Behavioral Actions of Antidepressants.

Selective serotonin reuptake inhibitors are the mostly widely used treatment for major depressive disorders and also are prescribed for several anxiety disorders. However, similar to most antidepressants, selective serotonin reuptake inhibitors suffer from two major problems: They only show beneficial effects after 2 to 4 weeks and only about 33% of patients show remission to first-line treatment. Thus, there is a considerable need for development of more effective antidepressants.

Regulation of N-type voltage-gated calcium channels and presynaptic function by cyclin-dependent kinase 5.

N-type voltage-gated calcium channels localize to presynaptic nerve terminals and mediate key events including synaptogenesis and neurotransmission. While several kinases have been implicated in the modulation of calcium channels, their impact on presynaptic functions remains unclear. Here we report that the N-type calcium channel is a substrate for cyclin-dependent kinase 5 (Cdk5).

Serotonin receptor expression along the dorsal-ventral axis of mouse hippocampus.

Using in situ hybridization, we describe, for the first time, the profiles of expression of serotonin receptors (Htr/5-HTR) along the dorsal-ventral axis of mouse hippocampus. cRNA probes for most Htrs, excluding Htr6, were used. All hippocampal subregions and the entorhinal cortex cells providing input into the hippocampus were examined.

Modeling treatment-resistant depression.

Depression is a polygenic and highly complex psychiatric disorder that is currently a major burden on society. Depression is highly heterogeneous in presentation and frequently exhibits high comorbidity with other psychiatric and somatic disorders. Commonly used treatments, such as selective serotonin reuptake inhibitors (SSRIs), are not ideal since only a subset of patients achieve remission.

Implications of the functional integration of adult-born hippocampal neurons in anxiety-depression disorders.

Adult neurogenesis in the dentate gyrus of the hippocampus has gained considerable attention as a cellular substrate for both the pathophysiology and treatment of depression. Overall, the studies of adult hippocampal neurogenesis are still in their infancy because most of them explore only one stage of this process. Importantly, given the built-in homeostatic mechanisms that act at each stage during the progression from stem cells to mature neurons (proliferation, differentiation, maturation, survival), it is very difficult to extrapolate the efficiency of a drug on adult neurogenesis from analysis of one stage alone.

Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression.

Understanding the physiopathology of affective disorders and their treatment relies on the availability of experimental models that accurately mimic aspects of the disease. Here we describe a mouse model of an anxiety/depressive-like state induced by chronic corticosterone treatment. Furthermore, chronic antidepressant treatment reversed the behavioral dysfunctions and the inhibition of hippocampal neurogenesis induced by corticosterone treatment.

Ndel1 controls the dynein-mediated transport of vimentin during neurite outgrowth.

Ndel1, the mammalian homologue of the Aspergillus nidulans NudE, is emergently viewed as an integrator of the cytoskeleton. By regulating the dynamics of microtubules and assembly of neuronal intermediate filaments (IFs), Ndel1 promotes neurite outgrowth, neuronal migration, and cell integrity (1-6). To further understand the roles of Ndel1 in cytoskeletal dynamics, we performed a tandem affinity purification of Ndel1-interacting proteins.

Cdk5 promotes synaptogenesis by regulating the subcellular distribution of the MAGUK family member CASK.

Synaptogenesis is a highly regulated process that underlies formation of neural circuitry. Considerable work has demonstrated the capability of some adhesion molecules, such as SynCAM and Neurexins/Neuroligins, to induce synapse formation in vitro. Furthermore, Cdk5 gain of function results in an increased number of synapses in vivo.

Cyclin-dependent kinase 5 permits efficient cytoskeletal remodeling--a hypothesis on neuronal migration.

Migration of neurons to their proper position underlies mammalian brain development. To remain on the proper path, a migrating neuron needs to detect various external signals and respond by efficiently remodeling its cytoskeleton. Cyclin-dependent kinase 5 (Cdk5), a member of the cyclin-dependent kinase family, regulates neuronal migration by phosphorylating a number of intracellular substrates.

Serine 732 phosphorylation of FAK by Cdk5 is important for microtubule organization, nuclear movement, and neuronal migration.

The serine/threonine kinase Cdk5 plays an essential role in neuronal positioning during corticogenesis, but the underlying mechanisms are unknown. In nonneuronal cells, the tyrosine kinase FAK is a major regulator of cell motility through focal adhesions. It is unclear whether FAK plays a role in brain development.