Christopher Kenneth Cain - US grants

DESCRIPTION (provided by applicant): Since Pavlov, conditional fear in mammals has been an important model of both associative learning and human anxiety. Briefly, animals rapidly learn to fear a neutral conditional stimulus (CS), such as a tone, when it is temporally paired with an aversive unconditional stimulus (US), typically a mild footshock. A subsequent exposure to the CS-alone elicits a robust conditional fear response (CR) in rodents, including freezing behavior. With repeated CS exposures the CR can strengthen (incubation) or weaken (extinction) depending on the temporal pattern of exposures. Extinction of fear is an active learning process resulting in the formation of an inhibitory memory that blocks fear expression. This proposal will focus on the cellular mechanisms underlying the induction of extinction memories. Aim 1 will attempt to define the minimum amount of CS exposure necessary to induce an extinction memory through a series of simple behavioral experiments. Aim 2 will investigate the potential role of amygdalar post-synaptic L-type voltage gated calcium channels (L-VGCC) in extinction memory induction, using systemic and local infusion of L-VGCC antagonists. Since extinction serves as the explicit model for behavior therapy of anxiety disorders, the findings may provide a foundation for improved psyhotherapies and adjunctive treatments.

[unreadable] DESCRIPTION (provided by applicant): Pavlovian conditioned fear is widely used to study the neural mechanisms of associative learning and anxiety. Conditioned fear is typically induced by pairing a neutral conditioned stimulus (CS) with an aversive unconditioned stimulus. Subsequent presentations of the CS elicit fear reactions. While this research is important, it neglects a class of learning with direct relevance to fear pathology and coping in humans: fear-motivated instrumental learning. The Escape From Fear (EFF) task was developed to study this learning separately from fear acquisition. In EFF, animals are presented with fear-eliciting CSs that terminate when they make a specific response. Thus, CS-termination is contingent upon active responding, or more formally, conditioned negative reinforcement supports response learning. This proposal outlines an investigation of the neural circuits responsible for EFF learning using an optimized EFF procedure, lesions, inactivations and single-unit recordings. The initial focus will be interactions between the amygdala, a nucleus critical for fear conditioning, and striatum, a region linked to instrumental learning. The results should further our understanding of fear learning with potentially important implications for human treatment. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Active coping strategies may be promoted during therapy for pathological anxiety because they: 1) give the patient control over exposure to aversive stimuli, 2) prevent fearful reactions and feelings, and 3) may produce a more permanent recovery. This is nicely modeled by active avoidance (AA) training where subjects learn to replace initial fear reactions with instrumental actions that prevent exposure to aversive stimuli. However, some excessively fearful subjects never master the AA task. Interestingly, this poor AA phenotype reflects a deficit in performance, rather than learning, since brain lesions that disrupt Pavlovian reactions rescue AA without further training (Choi et al., 2010; Lazaro.Munoz et al., 2010). Thus, defensive responding after AA training appears to depend on competition in fear processing circuits between Pavlovian and instrumental memories. This is consistent with observations that fearful reactions disappear once an AA response is acquired and reappear if the response is not available (Cain and LeDoux, 2007; Lovibond et al., 2008; Solomon and Wynne, 1954). The neural circuitry and mechanisms are well known for Pavlovian fear reactions but are poorly understood for AA, especially in humans. Even less is known about the neural circuits and transmitter systems mediating the competitive selection of active vs. reactive defensive responses. Our long term goal is to elucidate the brain systems, cells, molecules and physiological processes necessary for suppressing Pavlovian fear and establishing permanent active coping responses. We will begin with unbiased imaging of AA related brain activity in rats (c-fos expression) to identify critical response selection points inthe fear circuit. However, we will also test specific hypotheses about the role of amygdala and prefrontal cortex (PFC) norepinephrine in AA expression, given the importance of these regions and this neuromodulator to emotion and defensive behavior. Our objectives are to: 1) identify brain regions and cell populations where activity is associated with good vs. poor AA performance, and 2) determine whether adrenergic signaling influences action vs. reaction selection post training. Based on published and preliminary data, our main hypothesis is that ?-adrenergic receptor signaling in central amgydala (CE) opposes the expression of instrumental actions by promoting competing Pavlovian fear reactions. We will test this by injecting propranolol or isoproterenol into CE and assessing conditioned fear and AA in rats. We expect propranolol to suppress fear reactions and selectively enhance AA in poor avoiders, and isoproterenol to convert good avoiders to high freezing poor avoiders. Other candidate regions will be assessed similarly, but null effects are expected. If successful, these studies will identiy specific brain regions and signaling pathways critical for active coping. They may also suggest an innovative way to temporarily combine ¿.blockers with behavior therapy to establish permanent active coping strategies in anxious humans. Further, since avoidance can be maladaptive, these studies may identify a mechanism that is awry in pathological anxiety. PUBLIC HEALTH RELEVANCE: Instrumental active avoidance (AA) depends on the suppression of Pavlovian fear reactions, yet, the brain mechanisms mediating this response competition are unknown. In rats, we will identify critical brain regions and evaluate whether ?-adrenergic receptor signaling impedes AA by promoting competing Pavlovian fear reactions. Given that AA processes likely contribute to both the pathology (e.g. avoidance) and treatment (e.g. active coping) of anxiety, the findings may have therapeutic importance.

Abstract During active avoidance (AA), subjects learn to emit instrumental actions that escape conditioned threats and avoid pain. Little is known about the neural mechanisms mediating avoidance responses (ARs), because AA research stalled in the 1970s amid heated theoretical debates, inconsistent results with crude brain manipulations, and suggestions that Pavlovian processes were sufficient to explain ARs. This is unfortunate, as AA is the prototypical paradigm for studying aversively-motivated instrumental behavior, a class of defensive learning that almost certainly contributes to both adaptive and maladaptive active coping strategies. AA has several advantages as an adaptive coping/resilience mechanism: 1) it blunts fear and anxiety reactions, 2) it is less context-dependent and more persistent than fear extinction, and, unlike passive avoidance, 3) it allows subjects to remain engaged in environments that include danger. Conversely, maladaptive ARs may be particularly problematic because AA is extremely resistant to extinction and occasionally, paradoxically, enhanced by punishment (?vicious circle behavior?); processes that may be operating in human disorders ranging from anxiety (i.e. OCD) to addiction. Since AA likely reflects instrumental learning layered over previously acquired fear conditioning, the experiments in this proposal will leverage knowledge about Pavlovian fear and appetitive instrumental brain circuits to determine training conditions and neural mechanisms mediating cognitive vs. reflexive avoidance. Shuttlebox avoidance and a novel outcome-devaluation procedure will be used to examine the development of AA habits in rats. Experiments will focus on resolving conflicting predictions of our ?amygdala disengagement? model of habitual AA, derived from AA studies, and the ?parallel pathways? model of habit formation, derived from studies of positive reinforcement with drugs or food. Based on converging lines of preliminary data, we hypothesize that asymptotic ARs transition from goal-directed to habitual with time, as basolateral amygdala (BLA) disengages and competition between parallel circuits in dorsal striatum shifts to favor stimulus-response (S-R) over response-outcome (R-O) control. Explicit feedback cues will be included during AA training, and outcome-devaluation will be achieved by counterconditioning (pairing response-produced safety signals with shock). Our objectives are to determine 1) whether training- or time-dependent processes lead to habitual AA, 2) whether BLA projections to dorsomedial striatum mediate outcome-dependent AA, and 3) whether dorsolateral striatum (DLS) mediates habitual ARs independent of central amygdala. Chemogenetic suppression of neural activity in specific amygdalostriatal pathways will be used with devaluation to probe avoidance circuits. If successful, these studies will demonstrate that avoidance habits depend on a time- dependent disengagement of BLA and a shift towards DLS control of habitual ARs. Disrupting this S-R circuit in DLS while undermining safety signals could facilitate treatments aiming to break AA habits.