Erratum: Author Correction: Midbrain Circuit Regulation of Individual Alcohol Drinking Behaviors in Mice (Nature Communications (2017) 8 1 (2220))

The original version of this Article contained an error in the spelling of the author Scott Edwards, which was incorrectly given as Scott Edward. This has now been corrected in both the PDF and HTML versions of the Article

Rac1 is essential in cocaine-induced structural plasticity of nucleus accumbens neurons

Repeated cocaine administration increases the dendritic arborization of nucleus accumbens neurons, but the underlying signaling events remain unknown. Here, we show that repeated cocaine negatively regulates the active form of Rac1, a small GTPase that controls actin remodeling in other systems. We show further, using viral-mediated gene transfer, that overexpression of a dominant negative mutant of Rac1, or local knockout of Rac1 from floxed Rac1 mice, is sufficient to increase the density of immature dendritic spines on nucleus accumbens neurons, whereas overexpression of a constitutively active Rac1 mutant, or light activation of a photoactivatible form of Rac1, blocks the ability of repeated cocaine to produce this effect. Downregulation of Rac1 activity in nucleus accumbens likewise promotes behavioral responses to cocaine, with Rac1 activation producing the opposite effect. These findings establish an important role for Rac1 signaling in mediating structural and behavioral plasticity to cocaine

Midbrain circuit regulation of individual alcohol drinking behaviors in mice

Alcohol-use disorder (AUD) is the most prevalent substance-use disorder worldwide. There is substantial individual variability in alcohol drinking behaviors in the population, the neural circuit mechanisms of which remain elusive. Utilizing in vivo electrophysiological techniques, we find that low alcohol drinking (LAD) mice have dramatically higher ventral tegmental area (VTA) dopamine neuron firing and burst activity. Unexpectedly, VTA dopamine neuron activity in high alcohol drinking (HAD) mice does not differ from alcohol naive mice. Optogenetically enhancing VTA dopamine neuron burst activity in HAD mice decreases alcohol drinking behaviors. Circuit-specific recordings reveal that spontaneous activity of nucleus accumbens-projecting VTA (VTA-NAc) neurons is selectively higher in LAD mice. Specifically activating this projection is sufficient to reduce alcohol consumption in HAD mice. Furthermore, we uncover ionic and cellular mechanisms that suggest unique neuroadaptations between the alcohol drinking groups. Together, these data identify a neural circuit responsible for individual alcohol drinking behaviors

Sex, stress, and epigenetics: regulation of behavior in animal models of mood disorders

<p>Abstract</p> <p>Women have a higher incidence of stress related disorders including depression and generalized anxiety disorder, and epigenetic mechanisms likely contribute to this sex difference. Evidence from preclinical research suggests that epigenetic mechanisms are responsible for both sexual dimorphism of brain regions and sensitivity of the stress response. Epigenetic modifications such as DNA methylation and histone modifications can occur transgenerationally, developmentally, or in response to environmental stimuli such as stress exposure. This review will provide an overview of the various forms of epigenetic modifications observed in the central nervous system and will explain how these mechanisms contribute to a sexually dimorphic brain. It will also discuss the ways in which epigenetic alterations coincide with, and functionally contribute to, the behavioral response to stress across the lifespan. Ultimately, this review will focus on novel research utilizing animal models to investigate sex differences in epigenetic mechanisms that influence susceptibility to stress. Exploration of this relationship reveals epigenetic mechanisms with the potential to explain sexual dimorphism in the occurrence of stress related disorders.</p

Integrating Interleukin-6 into depression diagnosis and treatment

There is growing evidence of a relationship between inflammation and psychiatric illness. In particular, the cytokine Interleukin-6 (IL-6) has been linked to stress-related disorders such as depression and anxiety. Here we discuss evidence from preclinical and clinical studies examining the role of IL-6 in mood disorders. We focus on the functional role of peripheral and central release of IL-6 on the development of stress susceptibility and depression-associated behavior. By examining the contribution of both peripheral and central IL-6 to manifestations of stress-related symptomatology, we hope to broaden the way the field thinks about diagnosing and treating mood disorders

Longitudinal associations between dimensions of maltreatment and internalizing symptoms in late adolescence: The role of inflammation during the COVID-19 pandemic

Childhood adversity and depression have been linked with heightened inflammation. However, few longitudinal studies examine how dimensions of maltreatment (i.e., abuse and neglect) differentially impact pathways to heightened inflammation and internalizing symptoms. The present study examined effects of abuse and neglect on (1) internalizing symptoms through inflammation, and (2) on inflammation through internalizing symptoms across 3 years of adolescence in the context of the COVID-19 pandemic. In a sample of 78 adolescents, significant indirect effects revealed that childhood abuse, not neglect, significantly predicted future internalizing symptoms, which predicted future heighted C-reactive protein (CRP). Using prospective longitudinal data, these findings emphasize the importance of examining distinct forms of maltreatment in understanding the developmental pathways connecting early adversity, internalizing symptoms, and inflammation

Sex-Specific Effects of Chronic Fluoxetine Treatment on Neuroplasticity and Pharmacokinetics in Mice

Neurogenesis is a mechanism through which antidepressants may produce therapeutic effects. There is a dearth of information regarding the effects of antidepressants on neurogenesis and neurotrophin mobilization in females. This study examined sex differences in the alteration of cell proliferation and survival in multiple regions of the brain. Additional experiments examined brain-derived neurotrophic factor (BDNF) levels and pharmacokinetics of fluoxetine to determine whether they mediate sex differences. MRL/MpJ mice were treated with fluoxetine (5 and 10 mg/kg b.i.d.) for 21 days and received injections of 5-bromo-2′-deoxyuridine (200 mg/kg) to measure DNA synthesis. In the hippocampus, fluoxetine increased cell proliferation at both doses; females treated with 10 mg/kg produced more new cells than males. Fluoxetine did not alter survival in males, but 10 mg/kg reduced survival in females. In the frontal cortex, fluoxetine increased cell proliferation and survival in males treated with 10 mg/kg. In the cerebellum and amygdala, 10 mg/kg fluoxetine increased cell proliferation in both sexes but did not alter the incorporation of the new cells. Fluoxetine increased BDNF levels in the hippocampus of both sexes. BDNF levels correlated with cell proliferation in males but not females. Brain and plasma levels indicated that females metabolized fluoxetine faster than males and produced more of the metabolite norfluoxetine. These data suggest that fluoxetine acts on multiple areas of the brain to increase cell proliferation, and the pattern of activation differs between males and females. Sex-specific effects of fluoxetine on neurotrophin mobilization and pharmacokinetics may contribute to these differences in neural plasticity

Central and peripheral changes underlying susceptibility and resistance to social defeat stress - A proteomic profiling study

The social defeat mouse model is used as a preclinical model for major depressive disorder (MDD). This model is of interest, as mice subjected to chronic social defeat can be separated into stress susceptible (SS) and resilient (SR) subgroups that differ in defined behavioural and physiological characteristics. Here, we have carried out proteomic analyses of serum and brain samples from SS (n=12), SR (n=12) and unstressed control (n=12) mice, using two analytical platforms to gain insight into the underlying molecular pathways that distinguish these subgroups. Multiplex immunoassay profiling was performed using sera collected after 10 days of chronic social defeat. This analysis identified peripheral alterations in proteins mostly associated with inflammation in SS mice, whereas growth factors and hormones were changed predominantly in the SR subgroup. Label free liquid chromatography mass spectrometry (LC–MSE) profiling of frontal cortex revealed a significant increase in myelin-associated proteins [2′,3′-cyclic-nucleotide 3′-phosphodiesterase (CN37), mylein basic protein (MBP), and myelin proteolipid protein (MYPR)] in the SR group, suggesting that resilience to social stress might be mediated through activation of oligodendrogenesis. Taken together, these results provide the first proteomic evidence of differential effects on oligodendrocyte function between susceptible and resilient subgroups in the social defeat model and suggest that neuronal conductivity or central nervous system maintenance in the frontal cortex are involved in the adaptive response to stress. These changes appear to be reflected by serum alterations in inflammation and growth-related proteins, which could be used as biomarkers for predicting or monitoring stress response