Browsing by Subject "Nucleus accumbens"

Activation of monoaminergic receptors is essential to the mechanism by which psychostimulants and antidepressants induce changes in behavior. Although these drugs rapidly increase monoaminergic transmission, they need to be administered for several weeks or months in order to produce long-lasting alterations in behavior. This observation suggests that it is likely that molecular mechanisms downstream of receptor activation contribute to the effects of psychostimulants and antidepressants on behavior.

Recently, we and others have demonstrated that the methyl-CpG-binding protein 2 (MeCP2) contributes to both neural and behavioral adaptations induced by repeated psychostimulant exposure (Deng et al, 2010, Im et al, 2010). Psychostimulants induce rapid and robust phosphorylation of MeCP2 at Ser421 (pMeCP2), a site that is thought to modulate MeCP2-dependent chromatin regulation (Cohen et al, 2011), and this phosphorylation event is selectively induced in the GABAergic interneurons of the nucleus accumbens (NAc). In order to understand the signaling pathways that contribute to the pattern of pMeCP2 we observe, I characterized the monoaminergic signaling pathways that regulate pMeCP2. I found that activation of dopamine (DA) and serotonin (5-HT) transmission is sufficient to induce pMeCP2. The novel finding that drugs that activate serotonergic signaling induce pMeCP2 suggests that pMeCP2 may be involved in serotonergic mediated behaviors.

To determine the requirement of pMeCP2 in serotonergic mediated behaviors, I utilized mice that bear a knockin (KI) mutation that converts serine to alanine at 421 (S421A) (Cohen et al, 2011). After characterizing the behavioral phenotype of these mice, I conducted tests to assess anxiety- and depression-like behavior. I found that the KI mice do not display heightened anxiety in several assays. However, the KI mice exhibit depression-like behavior in the forced swim and tail suspension but show no differences compared to wild-type (WT) littermates in the sucrose preference test, suggesting that pMeCP2 may be implicated in the behavioral response to stressful stimuli.

Because we are interested in examining the role of pMeCP2 in the behavioral adaptations to chronic monoaminergic signaling, I then put the KI mice and their WT littermates through chronic social defeat stress, a behavioral paradigm in which repeated exposure to aggressive mice causes social avoidance that is reversed by chronic but not acute antidepressant treatment. Although the WT mice show an increase in social interaction following chronic imipramine treatment, the KI mice fail to show a behavioral response to chronic treatment. These data suggest that pMeCP2 may be implicated in the antidepressant action of chronic imipramine. Finally, investigation of the brain regions in which pMeCP2 may be contributing to the behavioral response to chronic imipramine treatment revealed that chronic but not acute imipramine treatment induces pMeCP2 in the lateral habenula (LHb), a brain region involved in the behavioral response to stress and reward. Together, these data implicate a novel role for pMeCP2 in depression-like behavior and the behavioral response to chronic antidepressant treatment.

Learning and memory are mediated by changes in synaptic and neuronal function within brain circuits, and is supported by dynamic waves of stimulus-dependent transcription in the nucleus of neurons. Stimulus-dependent transcription relies heavily on the epigenetic landscape of a given neuron, which is highly cell-type specific and can be further tuned by experience. Developments in genetic tools and methods to survey the entire transcriptome and epigenome have increased our ability to study stimulus-dependent transcription in diverse cell-types, including rare populations of interneurons. Application of these tools to addiction models, where long-lasting changes in behavior depend on stimulus-dependent transcription in diverse cell-types in multiple areas of the corticomesolimbic reward circuit, presents a particularly potent opportunity to increase our understanding of the functional consequences of stimulus-dependent transcription in diverse cell-types in a system that is highly relevant to human health. In the nucleus accumbens (NAc), parvalbumin-expressing (PV+) interneurons exert strong control over local circuit output and downstream behavior, including behavioral responses to drugs of abuse. Recent data from our lab suggest that perineuronal net (PNN) genes are a promising target for behaviorally-relevant, drug-dependent functional adaptations in this rare cell-type. In this dissertation, I use histological techniques in mouse tissue to validate in situ the heterogeneous transcriptional regulation of NAc PV+ interneurons and specific cell adhesion gene targets in response to psychostimulants, and explore the developmental and drug-dependent regulation of PNNs and the PNN gene Bcan. I use genetic and viral tools to specifically knockdown Bcan expression in NAc PV+ cells, and demonstrate that Bcan stabilizes their excitatory synaptic inputs even in adulthood and restricts the development of cocaine-context associations, showing that NAc PV+ interneurons and their PNNs play an important role in limiting the development of addiction-related behaviors. Finally, I use dCas9-mediated epigenetic editing to tune activity-dependent transcription of select rapid primary response genes, which are thought to interact with cell-type and cell-state dependent chromatin to coordinate later waves of stimulus-dependent transcription. I show that the fine details of activity-dependent transcription of rapid primary response genes resulting from chromatin state can lead to physiological changes in protein, and downstream neural physiology and behavior.

The nucleus accumbens core is believed to play an important role in regulating effort exertion. Effort can be explained as the energetic costs of an action relative to its long-term benefits. Using fixed-ratio schedules of reinforcement, different effort requirements can be imposed upon mice, as the cost per benefit is determined by these press-per-pellet ratios. Fixed-ratio schedules have long been used to study effort, and manipulations that impact more effortful behaviors to a greater extent have consistently been interpreted as demonstrating a decrease in the willingness to exert effort. For decades, in numerous studies, these effects have been consistently observed following manipulations that disrupt a specific region of the brain, the nucleus accumbens. In the accumbens there are two main types of neurons, the direct and indirect pathway neurons, that play different roles in behavior and project to different downstream structures. The accumbens has also traditionally been divided into two subregions, the core and the shell. Much of what is known about these circuits comes from work where the researchers inject drugs into the accumbens, but newer research methods have become far more precise. Optogenetic techniques, with improved temporal resolution, spatial resolution, and cell-type specificity, have become extremely useful tools across many areas of neurobiology; but optogenetics has yet to be applied specifically to questions regarding the regulation of effort. Here these questions have been addressed by combining optogenetics (activation or inhibition of direct or indirect pathway neurons in the core or shell) with various fixed-ratio procedures used to enforce distinct effort requirements. Pressing reductions elicited by activation of direct pathway neurons in the core were significant, but demonstrated no relationship with effort requirement. In contrast, effort-dependent pressing reductions were caused by activation of core indirect pathway neurons. Furthermore, this indirect effect was not caused by motor impairments or differences in appetite, because port-entry rates were maintained during these same sessions, regardless of ratio schedule. Although the direct pathway effect was effort-independent, activating these neurons in the core was also found to elicit persistent gnawing, upon inedible objects in the animals’ surroundings. In addition, significant increases in pressing were caused by inhibition of indirect pathway neurons in the core, and solely for the high-effort sessions. Lastly, optogenetic activation of indirect pathway neurons was found to elicit no behavioral effect when administered in the shell. These findings suggest that the willingness of animals to exert effort is being determined by the output of the indirect pathway projections from the core; and that these cells play this role somewhat exclusively, as the direct pathway is not regulating effort, and neither is the shell. But, indirect pathway neurons in the core determine willingness to exert effort on a moment-to-moment timescale, and this effort regulation process is bidirectional in nature, as demonstrated via bidirectional optogenetics. High output in these cells reduces the willingness to exert effort, whereas low output is associated with a greater willingness. These findings are novel, particularly the timescale of this effect, but in general they are in agreement with a large body of previous work. They also suggest that the two pathways and the two accumbal subregions play distinct roles in motivated behavior, and interestingly, core direct pathway activation can cause gnawing.