My general interest is in the cellular basis of learning and memory,and my lab focuses on understanding the cellular and molecular mechanisms underlying one particular type of learning, the extinction of Pavlovian fear conditioning. Classical, Pavlovian, fear conditioning is an important model both of learning and memory, and, of the pathogenesis of human anxiety disorders. Fear responses confer important protections from environmental threats, but are not always adaptive. Extinction is the gradual reduction of conditioned responding by persistent presentation of the conditional stimulus (i.e., tone; CS) without a paired unconditional stimulus (i.e., footshock; US), and it is the explicit basis for behavior therapy of anxiety disorders, and for cognitive behavioral therapy of depression, two psychotherapies of proven efficacy. Extinction is a form of learning, not erasure or passive forgetting, and is also one of the most elemental forms of learned inhibition. Even after complete extinction the original conditional response can return spontaneously with the passage of time, or be renewed by a change of context, demonstrating that the original memory remains, and that extinction only inhibits its expression. Despite its importance as a paradigm of inhibitory learning and its enormous relevance to human psychotherapy, little is known of the molecular or cellular mechanisms underlying the extinction of fear conditioning. Only a handful of papers have demontrated effects of drugs on extinction. Anatomically, only the amygdala has been unambiguously implicated in extinction. My laboratory is now focused on elucidating the neurotransmitters and second messenger systems involved in the extinction of fear conditioning, with the ultimate goal of developing adjunctive treatments to accelerate and facilitate the behavioral psychotherapy of anxiety disorders, psychotherapy in general, and inhibitory learning, the type of learning most dependent on intact frontal function. The underlying hypothesis governing the design of these experiments is that extinction should share mechanisms and molecules with other, well-studied forms of learning and of synaptic plasticity, such as long-term potentiation (LTP), and that differences from other forms of learning will be particularly interesting and relevant to inhibitory learning and to psychotherapy. Based on this hypothesis, we began with experiments to design an efficient extinction protocol, and immediately discovered an important difference between extinction and other forms of learning. We found that, unlike other forms of learning, extinciton is more efficient with temporally massed rather than spaced training. In exploring the basis of this finding, we discovered that the response to the CS is a compound of two opposing behavioral processes. Prolonged exposures do cause a weakening or decrease of responding, while shorter exposures not only cause less weakening, but actually cause increases of conditioned response, in this case behavioral freezing. The amount of behavioral extinction is the net outcome of these two opposing processes. This observation has allowed us to generate efficient protocols that generate either extinction or fear increase, and have allowed us to initiate investigations of the mechanisms for each of these behavioral processes. Our pharmacological investigations are at an early stage, but have already yielded interesting findings. While fear, and the fight or flight response, are famously related to adrenergic transmission, we have found that yohimbine, an adrenergic agonist that is anxiogenic in humans, facilitates extinction, while blocking the increases of fear with short CS exposures. Propanolol, an anxiolytic and amnestic beta-adrenergic blocker, facilitates both fear increases and the memory of that increase on subsequent days testing. The lab is now continuing with its behavioral and pharmacological dissection of extinction and the novel phenomenon of fear enhancement. We are also beginning to refine our questions in two ways: First, we are beginning to inject pharmacological agents directly in the amygdala and areas of prefrontal cortex, so that we can assign the drug effects we are seeing to defined anatomical locations. Second, we are beginning studies of amygdala LTP in brain slices in vitro, to attempt to attain a greater understanding of the cellular events underlying extinction in the amygdala.
Bredy Timothy W, Barad Mark The histone deacetylase inhibitor valproic acid enhances acquisition, extinction, and reconsolidation of conditioned fear Learning & memory (Cold Spring Harbor, N.Y.), 2008; 15(1): 39-45.
Bredy Timothy W, Wu Hao, Crego Cortney, Zellhoefer Jessica, Sun Yi E, Barad Mark Histone modifications around individual BDNF gene promoters in prefrontal cortex are associated with extinction of conditioned fear Learning & memory (Cold Spring Harbor, N.Y.), 2007; 14(4): 268-76.
Davis Michael, Barad Mark, Otto Michael, Southwick Stephen Combining pharmacotherapy with cognitive behavioral therapy: traditional and new approaches Journal of traumatic stress, 2006; 19(5): 571-81.
Barad Mark Divide and conquer: an L-type voltage-gated calcium channel subtype finds a role in conditioned fear Learning & memory (Cold Spring Harbor, N.Y.), 2006; 13(5): 560-1.
Barad Mark Is extinction of fear erasure or inhibition? Why both, of course Learning & memory (Cold Spring Harbor, N.Y.), 2006; 13(2): 108-9.
Barad Mark, Gean Po-Wu, Lutz Beat The role of the amygdala in the extinction of conditioned fear Biological psychiatry, 2006; 60(4): 322-8.
Cain Christopher K, Blouin Ashley M, Barad Mark Adrenergic transmission facilitates extinction of conditional fear in mice Learning & memory (Cold Spring Harbor, N.Y.), 2005; 11(2): 179-87.
Barad Mark Fear extinction in rodents: basic insight to clinical promise Current opinion in neurobiology, 2005; 15(6): 710-5.
Barad Mark, Blouin Ashley M, Cain Chris K Like extinction, latent inhibition of conditioned fear in mice is blocked by systemic inhibition of L-type voltage-gated calcium channels Learning & memory (Cold Spring Harbor, N.Y.), 2005; 11(5): 536-9.
Moccia Robert, Chen Dillon, Lyles Vlasta, Kapuya Estreya, E Yaping, Kalachikov Sergey, Spahn Christian M T, Frank Joachim, Kandel Eric R, Barad Mark, Martin Kelsey C An unbiased cDNA library prepared from isolated Aplysia sensory neuron processes is enriched for cytoskeletal and translational mRNAs The Journal of neuroscience : the official journal of the Society for Neuroscience, 2003; 23(28): 9409-17.
Barad Mark Later developments: molecular keys to age-related memory impairment Alzheimer disease and associated disorders, 2003; 17(3): 168-76.
Cain Christopher K, Blouin Ashley M, Barad Mark Temporally massed CS presentations generate more fear extinction than spaced presentations Journal of experimental psychology. Animal behavior processes, 2003; 29(4): 323-33.
Cain Chris K, Blouin Ashley M, Barad Mark L-type voltage-gated calcium channels are required for extinction, but not for acquisition or expression, of conditional fear in mice The Journal of neuroscience : the official journal of the Society for Neuroscience, 2002; 22(20): 9113-21.
Cain, C.K. and Barad, M. Fear extinction is more effective with massed than with distributed exposures to conditional stimuli and is modulated by b-adrenergic transmission, Submitted, 2001; .
Martin, KC Barad, M Kandel, ER Local protein synthesis and its role in synapse-specific plasticity Current opinion in neurobiology. , 2000; 10(5): 587-92.
Bach, ME Barad, M Son, H Zhuo, M Lu, YF Shih, R Mansuy, I Hawkins, RD Kandel, ER Age-related defects in spatial memory are correlated with defects in the late phase of hippocampal long-term potentiation in vitro and are attenuated by drugs that enhance the cAMP signaling pathway Proceedings of the National Academy of Sciences of the United States of America. , 1999; 96(9): 5280-5.
Barad, M Bourtchouladze, R Winder, DG Golan, H Kandel, E Rolipram, a type IV-specific phosphodiesterase inhibitor, facilitates the establishment of long-lasting long-term potentiation and improves memory Proceedings of the National Academy of Sciences of the United States of America. , 1998; 95(25): 15020-5.
Martin, KC Michael, D Rose, JC Barad, M Casadio, A Zhu, H Kandel, ER MAP kinase translocates into the nucleus of the presynaptic cell and is required for long-term facilitation in Aplysia Neuron. , 1997; 18(6): 899-912.
Abel, T Nguyen, PV Barad, M Deuel, TA Kandel, ER Bourtchouladze, R Genetic demonstration of a role for PKA in the late phase of LTP and in hippocampus-based long-term memory Cell. , 1997; 88(5): 615-26.
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