University of Vermont (P30 GM103498)
"Center for Neuroscience Excellence"

Pilot Project 2: "The Involvement of Lynx2 in Nicotinic Acetylcholine Receptor Signaling in the Prefrontal Cortex and Amygdala: Possible Relationship to Psychiatric Disorders"
Investigator: Donna Toufexis, Ph.D.

Aversive psychological stressors that trigger central fear systems also produce changes in autonomic nervous system (ANS) control cANSing sympathetic activation and parasympathetic withdrawal (i.e. reduced vagal tone). This relationship between cardiac vagal control and fear and anxiety has led to several models relating anxiety to vagal tone, and to autonomic adaptability and flexibility. Specifically, these models predict that high levels of ANS adaptive variability maintain cardiovascular (CV) health and that this is compromised by chronic or high anxiety states and therefore constitute a very real vulnerability towards CV illness in individuals who are suffering from psychopathologies like panic disorder, general anxiety disorder and post-traumatic stress disorder. Coordinated control of both the behavioral, as well as the ANS, response to threatening or aversive stimuli is mediated bilaterally within the forebrain by the amygdala. The amygdala receives significant inhibitory input from medial prefrontal cortex (mPFC) . Thus, alterations in amygdala neurotransmission would likely simultaneously affect both behavior and ANS activity.

 Nicotinic acetylcholine receptors (nAChRs) mediate a wide variety of functions in the nervous system. nAChRs are ligand-gated ion channels that mediate fast, excitatory neurotransmission in response to acetylcholine. In the peripheral nervous system cholinergic signaling drives autonomic ganglia and nAChR activation mediates vagal tone. In the adult CNS, projections from cholinergic neurons in the basal forebrain cholinergic system activate presynaptic nAChRs and influence the release of transmitters such as glutamate, GABA, serotonin, and dopamine, and thereby coordinate complex processing in the cerebral cortex governing processes including; attention, memory, cognition and emotional behavior. In fact, nAChR activation has been shown to modulate glutamate, GABA, and norepinephrine afferent to and within particular amygdalar sub-regions. Hence, the nAChR system may be a viable future candidate in which to explore the control of ANS adaptive variability related to the amygdala's co-regulation of emotional behavior.

 Nicotinic signaling can be modulated by proteins of the Ly-6/ urokinase-type plasminogen activator receptor (Ly6-UPAR) family, sometimes called Ly-6 neurotoxin-like (lynx) molecules. Murine lynx1 and lynx2 are tethered to the membrane and modulate nAChR activation and signaling. Transgenic knockout (KO) mice lacking lynx2 display greater responses to acetylcholine and display enhanced fear and anxiety in a number of behavioral tests including the amygdala-mediated Pavlovian fear-conditioning paradigm. Moreover, lynx2 mRNA is highly expressed though out the amygdala and in brain regions like the PFC. Furthermore, microarray gene analysis from mPFC punches taken after the extinction of fear-conditioning in mice showed increased lynx2 expression suggesting that reducing nAChR activation via lynx2 in projections to the amygdala are involved in fear extinction.

 The availability of transgenic lynx2 knockout mice at UVM allows a unique opportunity to further investigate this protein's role in modulating nAChRs afferents to, and nAChRs within, the amygdala and tying together the function of the nicotinic acetylcholine system with the amygdala in the emotional control of health.