Project 1:  How does serotonin modulate brain regions associated with anxiety-like behavior?

Substantial evidence suggests that the activation of serotonin systems alters anxiety-like behavior; however, the nature of the relationship between serotonin and anxiety is still unclear.  For example, selective-serotonin reuptake inhibitors (SSRIs), which elevate levels of serotonin in the central nervous system, have well-known therapeutic anxiety-reducing effects when administered chronically.  But the acute effects of these drugs often include increases in indices of anxiety.  Several nuclei associated with the central extended amygdala, including the bed nucleus of the stria terminalis (BNST) and central nucleus of the amygdala (CeA) have been suggested to mediate fear/anxiety-like behavior.  We are currently using behavioral, anatomical, and physiological techniques to determine how these brain regions respond to serotonin, in order to better understand the relationship between serotonin and anxiety.  Specific questions include:

Using brain microinfusion techniques combined with behavioral assays of anxiety, how does the activation/inactivation of specific serotonin receptor subtypes within the BNST alter anxiety-like behavior in the social interaction test, elevated plus maze, and acoustic startle response?

Using brain microinfusion techniques combined with immunohistochemistry, how does pharmacological activation of the serotonergic dorsal raphe nucleus alter activity in the central extended amygdala (as measured by c-fos expression)?

Using whole-cell patch clamp electrophysiology, how do BNST neurons respond to serotonin?  What receptors and effector systems mediate this response?

Exercise is therapeutic in the treatment of anxiety, and the effects of exercise may be mediated through changes in serotonin functioning.  We are currently investigating whether the effects of exercise on anxiety are mediated by serotonin changes in the BNST.  Metachlorophenylpiperazine  (mCPP), which is an agonist at 5-HT2B and 5-HT2C receptors (with some affinity at 5-HT2A receptors), increases signs of anxiety in both humans and animals.  The BNST has been implicated in mediating anxiety in a number of paradigms in rodents and primates.  Therefore, the BNST might an important brain region mediating the effects of serotonergic modulation on anxiety.  Single BNST neurons can respond to 5-HT with excitation and/or inhibition, and mCPP injected into the BNST is anxiogenic likely because this drug selectively activates the excitatory response on these neurons, which is mediated, in part, by the 5-HT2 family of receptors.  Consistent with reports in humans, we have shown that voluntary exercise is anxiolytic in many anxiety models in animals.  Importantly, voluntary exercise reduces the increases in anxiety observed after mCPP. These studies are being conducted in a collaborative effort with Professor Bill Falls and the Falls Laboratory in the Department of Psychology. Specific question include:

Using brain microinfusion techniques combined with behavioral assays of anxiety, are the effects of intra-BNST mCPP mediated by 5-HT2A or 5-HT2C receptors?

Does voluntary exercise on the dose-response curve of intra-BNST mCPP?

Using whole-cell patch clamp electrophysiology, Does voluntary exercise shift the population of serotonin responses to the favor inhibition, and does exercise alter the dose-response curve to exogenously applied mCPP?

Funded by a grant from the National Institute of Mental Health

Although evidence suggests that chronic stress is important to the etiology of anxiety disorders, ,the mechanisms by which stress alters brain anxiety circuits are still unknown.  Substantial evidence has implicated the BNST as a critical structural node mediating anxiety-like behavior in humans and animals.  The BNST organizes central and peripheral stress responding to unpredictable and/or persistent threats, and sustained exposure to these stressful events has been argued to result in maladaptive BNST functioning that could underlie anxiety disorders.  Consistent with this hypothesis, previous reports have shown that chronic stress-induced BNST neuroplasticity leads to enhanced excitability within BNST networks to produce heightened anxiety states.  Pituitary adenylate cyclase activating polypeptides (PACAP) have acute neurotransmitter functions in neuronal excitability, long term neurotrophic properties in neuroplasticity, and appear to be key components in stress signaling. In collaboration with Professor Victor May in the Departiment of Anatomy and Neurobiology and Professor Bill Falls and the Falls Laboratory in the Department of Psychology, we are currently determiningthe role of BNST PACAP in mediating stress-induce anxiety-like behavior. Specific questions include:

Does chronic stress increase the expression of PACAP and its cognate PAC1 receptor uniquely within the BNST, and is intra-BNST PACAP injection anxiogenic?

Does PACAP signaling mediate plasticity within the BNST.

Funded by a grant from UVM's Vice President for Research and Graduate Studies (Research Opportunities Grant Program)