The experience of an aversive event produces in animals and in humans profound and diffuse changes within the brain. For example, in the healthy brain, exposure to an aversive event requires balancing the expression of defensive and non-defensive behaviors. Deficits in the formation, maintenance and flexibility of this balance can lead to mental-health problems, such as anxiety disorders and post-traumatic stress disorder. Therefore, characterizing the mechanisms by which experience regulates the expression of multiple behaviors represents a critical step to understand medical conditions affecting millions of Americans. In the marine mollusk Aplysia californica, exposure to aversive stimuli induces the concurrent modulation of defensive and non-defensive behaviors. Specifically, aversive stimuli induce two opposite behavioral changes: a learned enhancement of defensive responses (i.e., sensitization) and a suppression of feeding behavior. Sensitization and suppression of feeding share analogous time courses that depend on the amount of aversive stimulation. Whereas the cellular and molecular mechanisms underlying sensitization in Aplysia have been extensively characterized, those underlying the suppression of feeding remain largely unknown. The PI's lab has recently begun to analyze the cellular and biochemical underpinning of the suppression of feeding induced by aversive stimuli. At the cellular level, the suppression of feeding is accompanied by a decreased excitability of a decision-making neuron (B51) critical for the expression of feeding. Recent evidence indicates that suppression of feeding and decreased B51 excitability are, at least in part, mediated by the cyclic GMP signaling cascade. In addition, serotonin, which mediates sensitization in Aplysia, does not alter either feeding or B51 excitability, suggesting that changes in the defensive and feeding neural circuits produced by aversive stimuli may be mediated by distinct and/or multiple neuromodulator(s). Using a combination of in vivo and in vitro procedures, this project will: 1) characterize the intracellular signals responsible for feeding suppression of and B51 decreased excitability by examining the role of the cGMP signaling cascade;2) identify which neuromodulator mediates the suppression of feeding and decreased B51 excitability by investigating the contribution of a nitric oxide dependent pathway and 3) explore the relationship between sensitization and feeding suppression, by attempting to """"""""uncouple"""""""" these two behavioral changes by manipulating the animal's motivational state and extending the exposure to aversive stimuli. The experiments outlined in this project propose a detailed analysis of the mechanisms responsible for the modulation of multiple behaviorally-relevant neural circuits by experience. This line of research in Aplysia will contribute to the understanding of how non-defensive neural circuits change their activity and their relations with defensive circuits in response to aversive stimuli in more complex animals, including humans.
By characterizing the effects of aversive stimuli on defensive and non-defensive behaviors in a simple organism, such as Aplysia, this project will address the critical need to comprehend the basic mechanisms by which experience regulates the expression of multiple behaviors and their neural circuits. The findings obtained from this line of work in Aplysia will elucidate the logic behind the experience-induced modulation of neural circuits in more complex animals, including humans. This knowledge may ultimately help achieve a better understanding of forms of mental illness, such as post-traumatic stress disorder, in which the balance between defensive and non-defensive behaviors is disrupted.
|Weisz, Harris A; Wainwright, Marcy L; Mozzachiodi, Riccardo (2017) A novel in vitro analog expressing learning-induced cellular correlates in distinct neural circuits. Learn Mem 24:331-340|