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The Nathan S. Kline Institute for Psychiatric Research

Emotional Brain Institute (EBI)

Laboratories

Sears Lab

Lab Name
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Fear and anxiety disorders involve dysfunction in brain systems that evolved to promote survival in life or death situations. These brain systems control the ‘fight or flight’ response, which is inappropriately triggered in psychiatric disorders such as PTSD (post traumatic stress disorder) and various forms of phobic disorders. For example, innocuous environmental stimuli, like a car backfiring or a car honking may cause exaggerated behavioral and physiological responses in combat veterans suffering from PTSD. As these reactions become more frequent, individuals begin to withdraw from society; they lose sleep, abuse drugs and, in the worst cases, end their own life.

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We use a simple procedure referred to as Pavlovian threat conditioning (PTC) to create ‘emotional memories’ in rodents so we can study the cells, circuits and molecules that underlie responses to threat in health and disease. We discovered that a population of neurons in the hypothalamus, known as orexin or hypocretin cells, are important for the formation of implicit memories about cues that warn of danger. We speculate that the activity of these orexin cells may strongly influence normal reactions, as well as pathological overreactions, to environmental stimuli.

Another procedure we use in the lab, Signaled Active Avoidance (SAA), allows us to study the brain mechanisms underlying the avoidance of threat or harm. Using this procedure, we found that interactions between the amygdala and the nucleus accumbens are important for driving avoidance behaviors.

We will continue to study the role of orexin cells and amygdala-accumbens interactions, with the goal being that with better understanding of these circuits we may find better treatments for individuals suffering from anxiety and stress-related disorders.

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Current Investigations
  • The Role of The Orexin System in Responding to Threat: The orexin system controls many behaviors thought to underlie fear and anxiety disorders in humans. We are currently using advanced molecular techniques to characterize genetic activity in orexin neurons. We hypothesize that molecular-genetic signature differences in orexin neurons underlie individual differences in defensive responding to threatening stimuli. In conjunction, we are also looking at brain targets of orexin neurons and how changes in orexin release at axon terminals can affect their responses to threat.
  • Neural Circuitry Underlying Signaled Active Avoidance (SAA): In SAA, subjects respond during a signal that predicts threat, to terminate the threat. Although avoidance can be maladaptive, the learning processes important for SAA are similar to those necessary for adaptive active coping. Using behavioral pharmacology techniques we have determined that the amygdala communicates information to the ventral striatum (the nucleus accumbens) to initiate appropriate responding to signaled threats. Related to this, we are currently running SAA experiments in combination with chemogenetics and optogenetics to test the hypothesis that the dorsal striatum is important for maladaptive habit formation.