Behavioral and Transcriptomic Changes Following Brain-Specific Loss of Noradrenergic Transmission.

Noradrenaline (NE) plays an integral role in shaping behavioral outcomes including anxiety/depression, fear, learning and memory, attention and shifting behavior, sleep-wake state, pain, and addiction. However, it is unclear whether dysregulation of NE release is a cause or a consequence of maladaptive orientations of these behaviors, many of which associated with psychiatric disorders. To address this question, we used a unique genetic model in which the brain-specific vesicular monoamine transporter-2 (VMAT2) gene expression was removed in NE-positive neurons disabling NE release in the entire brain. We engineered VMAT2 gene splicing and NE depletion by crossing floxed VMAT2 mice with mice expressing the Cre-recombinase under the dopamine ß-hydroxylase (DBH) gene promotor. In this study, we performed a comprehensive behavioral and transcriptomic characterization of the VMAT2DBHcre KO mice to evaluate the role of central NE in behavioral modulations. We demonstrated that NE depletion induces anxiolytic and antidepressant-like effects, improves contextual fear memory, alters shifting behavior, decreases the locomotor response to amphetamine, and induces deeper sleep during the non-rapid eye movement (NREM) phase. In contrast, NE depletion did not affect spatial learning and memory, working memory, response to cocaine, and the architecture of the sleep-wake cycle. Finally, we used this model to identify genes that could be up- or down-regulated in the absence of NE release. We found an up-regulation of the synaptic vesicle glycoprotein 2c (SV2c) gene expression in several brain regions, including the locus coeruleus (LC), and were able to validate this up-regulation as a marker of vulnerability to chronic social defeat. The NE system is a complex and challenging system involved in many behavioral orientations given it brain wide distribution. In our study, we unraveled specific role of NE neurotransmission in multiple behavior and link it to molecular underpinning, opening future direction to understand NE role in health and disease.

Innate sensitivity to stress facilitates inflammation, alters metabolism and shortens lifespan in a mouse model of social hierarchy.

It is known that stress alters homeostasis and may lead to accelerated aging. However, little is known about the contribution of innate susceptibility to stress to the deterioration of physiological functions, acceleration of aging and developing of age-related diseases. By using socially-submissive stress susceptible (Sub) and socially-dominant stress resilient (Dom) selectively bred mouse model we observed a marked reduction in the lifespan of both male and female Sub mice. We found that innate susceptibility to stress correlates with chronic inflammation, development of splenomegaly and a significant increase in the levels of circulating pro-inflammatory cytokines IL-1ß and IL-6. Furthermore, Sub mice showed a marked hypoglycemia, reduction of insulin levels, increase in GSK3 activity and elevation of IGF-1 serum levels, as well as low skin surface temperature and body weight. Interestingly, lifelong exposure of Sub mice to chronic mild stress did not further reduce their lifespan, indicating a high level of intrinsic stress. Taken together, our data reveal that social submissiveness coupled with innate stress sensitivity coincides with inflammation, leading to the deterioration of physiological functions and early aging independent of whether an individual is exposed to stress or not.

Seasonality and BDNF polymorphism influences depression outcome in patients with atopic dermatitis and psoriasis.

OBJECTIVES: To examine the effect of seasonality and rs6265 genotype on depression outcome and brain-derived neurotrophic factor (BDNF) level with dermatitis patients from onset through remission. METHODS: Atopic dermatitis (AD, 56) and psoriasis (PS, 33) patients and healthy controls (HC, 49) were recruited over the 2014 calendar year. Patients were subdivided by immunoglobulin E (IgE) sensitivity (AD only), season and rs6265 genotype. Assessments were performed at onset and week 10 (Hamilton Depression Rating Scale [HAM-D], SCORAD/PASI, IgE, BDNF). Patients received standard corticosteroid and antihistamine interventions. RESULTS: All patients responded to corticosteroid treatment. Seasonally differential outcomes were observed in all groups. HAM-D was elevated at onset and improved over 10 weeks: AD cohort 1 (autumn/winter, AD-1) patients improved and AD cohort 2 (spring/summer, AD-2) patients remained elevated. BDNF levels were elevated in AD and seasonal differential: AD-2 declined at 10 weeks, whereas AD-1 remained high (intrinsic AD) or elevated further (extrinsic AD). PS cohort 2 declined to below control at 10 weeks. AD Val/Val had persistently elevated HAM-D and AD Val/Met were either normal (AD-1) or persistently elevated (AD-2). CONCLUSIONS: Findings presented here suggest a strong influence of seasonality on depression outcome and BDNF expression in AD and PS and likely reflect separate patient populations which differentially respond to environment-based stressors.

Electrical stimulation of the vmPFC serves as a remote control to affect VTA activity and improve depressive-like behavior.

Despite progress in elucidating mechanisms of depression, the efficacy of different treatments remains inadequate. Recent small-scale clinical studies suggested anti-depressant treatment using deep brain stimulation (DBS) of the ventral capsule/ventral striatum or subgenual cingulate cortex (SCC), yet controlled, multi-center trials were unsuccessful. We recently suggested the ventral tegmental area (VTA) as an important intersection for treating depression. We also found that stimulation of the VTA of a genetic rat model of depression (Flinders Sensitive Line (FSL) rats) with a programmed pattern designed to mimic the burst firing of normal rats decreases depressive-like behavior. Herein, we examined the possibility of reaching the VTA - located deep in the brain stem - through its direct connection to the ventro-medial prefrontal cortex (vmPFC), which parallels the human SCC. Thus, we compared treatment of FSLs with modified versions of DBS - either chronic-intermittent low-frequency electrical stimulation of the vmPFC, or patterned acute electrical stimulation (pAES), which integrates transcranial magnetic stimulation properties, namely, bursts of pulse trains and low frequency stimulation, applied to the VTA. We found that stimulation of the vmPFC (20Hz, 15min/day, 10days) improved depressive-like behavior and VTA local field potential (LFP) activity of FSLs, yet it had only a partial long-term effect on behavior. In particular, vmPFC stimulation decreased theta band activity, which correlated with the improvement in depressive-like behavior of all treated FSLs at day 1, and in ~50% of treated FSLs at day 28 post treatment. pAES of the VTA (10Hz, 20min) caused significant, long-term improvement of depressive-like behavior of FSLs, concurrently with normalizing intra-VTA LFP activity, and increasing VTA LFP synchronicity and hippocampal BDNF mRNA levels. Thus, although low-frequency electrical stimulation of the PFC alters VTA activity, leading to attenuation of depressive-like manifestations, a specific stimulation pattern affecting VTA cell programming is important for long-term efficacy.

Synapsin IIb as a functional marker of submissive behavior.

Dominance and submissiveness are important functional elements of the social hierarchy. By employing selective breeding based on a social interaction test, we developed mice with strong and stable, inheritable features of dominance and submissiveness. In order to identify candidate genes responsible for dominant and submissive behavior, we applied transcriptomic and proteomic studies supported by molecular, behavioral and pharmacological approaches. We clearly show here that the expression of Synapsin II isoform b (Syn IIb) is constitutively upregulated in the hippocampus and striatum of submissive mice in comparison to their dominant and wild type counterparts. Moreover, the reduction of submissive behavior achieved after mating and delivery was accompanied by a marked reduction of Syn IIb expression. Since submissiveness has been shown to be associated with depressive-like behavior, we applied acute SSRI (Paroxetine) treatment to reduce submissiveness in studied mice. We found that reduction of submissive behavior evoked by Paroxetine was paired with significantly decreased Syn IIb expression. In conclusion, our findings indicate that submissiveness, known to be an important element of depressive-like behavioral abnormalities, is strongly linked with changes in Syn IIb expression.