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Proinflammatory cytokines, such as IL-1β, have been implicated in the cellular and behavioral effects of stress and in mood disorders, although the downstream signaling pathways underlying these effects have not been determined. In the present study, we demonstrate a critical role for NF-κB signaling in the actions of IL-1β and stress. Stress inhibition of neurogenesis in the adult hippocampus, which has been implicated in the prodepressive effects of stress, is blocked by administration of an inhibitor of NF-κB. Further analysis reveals that stress activates NF-κB signaling and decreases proliferation of neural stem-like cells but not early neural progenitor cells in the adult hippocampus. We also find that depressive-like behaviors caused by exposure to chronic stress are mediated by NF-κB signaling. Together, these data identify NF-κB signaling as a critical mediator of the antineurogenic and behavioral actions of stress and suggest previously undescribed therapeutical targets for depression.

Normal development of cortical circuits, including experience-dependent cortical maturation and plasticity, requires precise temporal regulation of gene expression and molecular signaling. Such regulation, and the concomitant impact on plasticity and critical periods, is hypothesized to be disrupted in neurodevelopmental disorders. A protein that may serve such a function is the MET receptor tyrosine kinase, which is tightly regulated developmentally in rodents and primates, and exhibits reduced cortical expression in autism spectrum disorder and Rett Syndrome. We found that the peak of MET expression in developing mouse cortex coincides with the heightened period of synaptogenesis, but is precipitously downregulated prior to extensive synapse pruning and certain peak periods of cortical plasticity. These results reflect a potential on–off regulatory synaptic mechanism for specific glutamatergic cortical circuits in which MET is enriched. In order to address the functional significance of the ‘off’ component of the proposed mechanism, we created a controllable transgenic mouse line that sustains cortical MET signaling. Continued MET expression in cortical excitatory neurons disrupted synaptic protein profiles, altered neuronal morphology, and impaired visual cortex circuit maturation and connectivity. Remarkably, sustained MET signaling eliminates monocular deprivation-induced ocular dominance plasticity during the normal cortical critical period; while ablating MET signaling leads to early closure of critical period plasticity. The results demonstrate a novel mechanism in which temporal regulation of a pleiotropic signaling protein underlies cortical circuit maturation and timing of cortical critical period, features that may be disrupted in neurodevelopmental disorders.

Expression of TET1 dioxygenase, which catalyzes the conversion of 5-methylcytosine to 5-hydroxymethylcytosine, is downregulated by repeated cocaine administration in mouse nucleus accumbens, where it controls cocaine reward. Genome-wide mapping of 5-hydroxymethylcytosine in this brain region reveals novel modes of epigenetic regulation by cocaine. Ten-eleven translocation (TET) enzymes mediate the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), which is enriched in brain, and its ultimate DNA demethylation. However, the influence of TET and 5hmC on gene transcription in brain remains elusive. We found that ten-eleven translocation protein 1 (TET1) was downregulated in mouse nucleus accumbens (NAc), a key brain reward structure, by repeated cocaine administration, which enhanced behavioral responses to cocaine. We then identified 5hmC induction in putative enhancers and coding regions of genes that have pivotal roles in drug addiction. Such induction of 5hmC, which occurred similarly following TET1 knockdown alone, correlated with increased expression of these genes as well as with their alternative splicing in response to cocaine administration. In addition, 5hmC alterations at certain loci persisted for at least 1 month after cocaine exposure. Together, these reveal a previously unknown epigenetic mechanism of cocaine action and provide new insight into how 5hmC regulates transcription in brain in vivo .

Depression is the leading cause of disability and produces enormous health and economic burdens. Current treatment approaches for depression are largely ineffective and leave more than 50% of patients symptomatic, mainly because of non-selective and broad action of antidepressants. Thus, there is an urgent need to design and develop novel therapeutics to treat depression. Given the heterogeneity and complexity of the brain, identification of molecular mechanisms within specific cell-types responsible for producing depression-like behaviors will advance development of therapies. In the reward circuitry, the nucleus accumbens (NAc) is a key brain region of depression pathophysiology, possibly based on differential activity of D1- or D2- medium spiny neurons (MSNs). Here we report a circuit- and cell-type specific molecular target for depression, Shisa6, recently defined as an AMPAR component, which is increased only in D1-MSNs in the NAc of susceptible mice. Using the Ribotag approach, we dissected the transcriptional profile of D1- and D2-MSNs by RNA sequencing following a mouse model of depression, chronic social defeat stress (CSDS). Bioinformatic analyses identified cell-type specific genes that may contribute to the pathogenesis of depression, including Shisa6. We found selective optogenetic activation of the ventral tegmental area (VTA) to NAc circuit increases Shisa6 expression in D1-MSNs. Shisa6 is specifically located in excitatory synapses of D1-MSNs and increases excitability of neurons, which promotes anxiety- and depression-like behaviors in mice. Cell-type and circuit-specific action of Shisa6, which directly modulates excitatory synapses that convey aversive information, identifies the protein as a potential rapid-antidepressant target for aberrant circuit function in depression.

Chronic social-defeat stress increases phasic firing of ventral tegmental area (VTA) neurons and increases the amount of BDNF in the nucleus accumbens (NAc). The authors show that increased activity of NAc-projecting VTA neurons is sufficient to increase the amount of BDNF in the NAc, an effect that depends on CRF signaling in the NAc. Mechanisms controlling release of brain-derived neurotrophic factor (BDNF) in the mesolimbic dopamine reward pathway remain unknown. We report that phasic optogenetic activation of this pathway increases BDNF amounts in the nucleus accumbens (NAc) of socially stressed mice but not of stress-naive mice. This stress gating of BDNF signaling is mediated by corticotrophin-releasing factor (CRF) acting in the NAc. These results unravel a stress context–detecting function of the brain's mesolimbic circuit.

Brain-derived neurotrophic factor (BDNF) is a key positive regulator of neural plasticity, promoting, for example, the actions of stimulant drugs of abuse such as cocaine. We discovered a surprising opposite role for BDNF in countering responses to chronic morphine exposure. The suppression of BDNF in the ventral tegmental area (VTA) enhanced the ability of morphine to increase dopamine (DA) neuron excitability and promote reward. In contrast, optical stimulation of VTA DA terminals in nucleus accumbens (NAc) completely reversed the suppressive effect of BDNF on morphine reward. Furthermore, we identified numerous genes in the NAc, a major target region of VTA DA neurons, whose regulation by BDNF in the context of chronic morphine exposure mediated this counteractive function. These findings provide insight into the molecular basis of morphine-induced neuroadaptations in the brain's reward circuitry.

Genetic risk factors for neurodegenerative disorders, such as Alzheimer’s disease (AD), are expressed throughout the life span. How these risk factors affect early brain development and function remain largely unclear. Analysis of animal models with high constructive validity for AD, such as the 5xFAD mouse model, may provide insights on potential early neurodevelopmental effects that impinge on adult brain function and age-dependent degeneration. The 5XFAD mouse model over-expresses human amyloid precursor protein (APP) and presenilin 1 (PS1) harboring five familial AD mutations. It is unclear how the expression of these mutant proteins affects early developing brain circuits. We found that the prefrontal cortex (PFC) layer 5 (L5) neurons in 5XFAD mice exhibit transgenic APP overloading at an early post-weaning age. Impaired synaptic plasticity (long-term potentiation, LTP) was seen at 6–8 weeks age in L5 PFC circuit, which was correlated with increased intracellular APP. APP overloading was also seen in L5 pyramidal neurons in the primary visual cortex (V1) during the critical period of plasticity (4–5 weeks age). Whole-cell patch clamp recording in V1 brain slices revealed reduced intrinsic excitability of L5 neurons in 5XFAD mice, along with decreased spontaneous miniature excitatory and inhibitory inputs. Functional circuit mapping using laser scanning photostimulation (LSPS) combined with glutamate uncaging uncovered reduced excitatory synaptic connectivity onto L5 neurons in V1, and a more pronounced reduction in inhibitory connectivity, indicative of altered excitation and inhibition during VC critical period. Lastly, in vivo single-unit recording in V1 confirmed that monocular visual deprivation-induced ocular dominance plasticity during critical period was impaired in 5XFAD mice. Our study reveals plasticity deficits across multiple cortical regions and indicates altered early cortical circuit developmental trajectory as a result of mutant APP/PS1 over-expression.

Repeated exposure to cocaine increases dendritic spine density on nucleus accumbens (NAc) neurons. Here the authors show that the small GTPase Rac1 is necessary and sufficient for cocaine-induced behavior and spine changes in NAc neurons, adding support for a causal role for structural plasticity in cocaine-induced behavior. Repeated cocaine administration increases the dendritic arborization of nucleus accumbens neurons, but the underlying signaling events remain unknown. Here we show that repeated exposure to cocaine negatively regulates the active form of Rac1, a small GTPase that controls actin remodeling in other systems. Further, we show, using viral-mediated gene transfer, that overexpression of a dominant negative mutant of Rac1 or local knockout of Rac1 is sufficient to increase the density of immature dendritic spines on nucleus accumbens neurons, whereas overexpression of a constitutively active Rac1 or light activation of a photoactivatable form of Rac1 blocks the ability of repeated cocaine exposure to produce this effect. Downregulation of Rac1 activity likewise promotes behavioral responses to cocaine exposure, with activation of Rac1 producing the opposite effect. These findings establish that Rac1 signaling mediates structural and behavioral plasticity in response to cocaine exposure.

Comprehensive analysis of epigenetic regulation demonstrates a series of complex, interacting chromatin mechanisms by which chronic exposure to opiates downregulates Bdnf gene transcription in the ventral tegmental area. This regulatory cascade is also shown to play a role in controlling opiate-induced behavioral plasticity. Brain-derived neurotrophic factor (BDNF) has a crucial role in modulating neural and behavioral plasticity to drugs of abuse. We found a persistent downregulation of exon-specific Bdnf expression in the ventral tegmental area (VTA) in response to chronic opiate exposure, which was mediated by specific epigenetic modifications at the corresponding Bdnf gene promoters. Exposure to chronic morphine increased stalling of RNA polymerase II at these Bdnf promoters in VTA and altered permissive and repressive histone modifications and occupancy of their regulatory proteins at the specific promoters. Furthermore, we found that morphine suppressed binding of phospho-CREB (cAMP response element binding protein) to Bdnf promoters in VTA, which resulted from enrichment of trimethylated H3K27 at the promoters, and that decreased NURR1 (nuclear receptor related-1) expression also contributed to Bdnf repression and associated behavioral plasticity to morphine. Our findings suggest previously unknown epigenetic mechanisms of morphine-induced molecular and behavioral neuroadaptations.

Optogenetic induction of phasic, but not tonic, firing in VTA dopamine neurons induces susceptibility to stress in mice undergoing a subthreshold social-defeat paradigm and in previously resilient mice that have been subjected to repeated social-defeat stress, and this effect is projection-pathway specific. Role of VTA neurons in depression Dopaminergic neurons in the ventral tegmental area (VTA) are involved in reward processing but also in mediating stress responses. Two papers from Ming-Hu Han and Karl Deisseroth's laboratories demonstrate the effects of specifically manipulating these neurons on stress-evoked behaviours. Han and colleagues probe the functional effects of different patterns of activity during social defeat, an acutely stressful experience. Manipulation of phasic, but not tonic, activity of certain populations of VTA neurons renders previously resilient mice susceptible to stress. Deisseroth and colleagues examine the effects of manipulating VTA neuron activity on behavioural effects and circuit alterations caused by exposure to long-term, chronic stress. These studies emphasize the behavioural importance of circuit-specific firing patterns and provide insights into developing novel therapeutics for the treatment of depression. Ventral tegmental area (VTA) dopamine neurons in the brain’s reward circuit have a crucial role in mediating stress responses 1 , 2 , 3 , 4 , including determining susceptibility versus resilience to social-stress-induced behavioural abnormalities 5 . VTA dopamine neurons show two in vivo patterns of firing: low frequency tonic firing and high frequency phasic firing 6 , 7 , 8 . Phasic firing of the neurons, which is well known to encode reward signals 6 , 7 , 9 , is upregulated by repeated social-defeat stress, a highly validated mouse model of depression 5 , 8 , 10 , 11 , 12 , 13 . Surprisingly, this pathophysiological effect is seen in susceptible mice only, with no apparent change in firing rate in resilient individuals 5 , 8 . However, direct evidence—in real time—linking dopamine neuron phasic firing in promoting the susceptible (depression-like) phenotype is lacking. Here we took advantage of the temporal precision and cell-type and projection-pathway specificity of optogenetics to show that enhanced phasic firing of these neurons mediates susceptibility to social-defeat stress in freely behaving mice. We show that optogenetic induction of phasic, but not tonic, firing in VTA dopamine neurons of mice undergoing a subthreshold social-defeat paradigm rapidly induced a susceptible phenotype as measured by social avoidance and decreased sucrose preference. Optogenetic phasic stimulation of these neurons also quickly induced a susceptible phenotype in previously resilient mice that had been subjected to repeated social-defeat stress. Furthermore, we show differences in projection-pathway specificity in promoting stress susceptibility: phasic activation of VTA neurons projecting to the nucleus accumbens (NAc), but not to the medial prefrontal cortex (mPFC), induced susceptibility to social-defeat stress. Conversely, optogenetic inhibition of the VTA–NAc projection induced resilience, whereas inhibition of the VTA–mPFC projection promoted susceptibility. Overall, these studies reveal novel firing-pattern- and neural-circuit-specific mechanisms of depression.