Isomorphisms between psychological processes and neural mechanisms: From stimulus elements to genetic markers of activity

Traditional learning theory has developed models that can accurately predict and describe the course of learned behavior. These “psychological process” models rely on hypothetical constructs that are usually thought to be not directly measurable or manipulable. Recently, and mostly in parallel, the neural mechanisms underlying learning have been fairly well elucidated. The argument in this essay is that we can successfully uncover isomorphisms between process and mechanism and that this effort will help advance our theories about both processes and mechanisms. We start with a brief review of error-correction circuits as a successful example. Then we turn to the concept of stimulus elements, where the conditional stimulus is hypothesized to be constructed of a multitude of elements only some of which are sampled during any given experience. We discuss such elements with respect to how they explain acquisition of associative strength as an incremental process. Then we propose that for fear conditioning, stimulus elements and basolateral amygdala projection neurons are isomorphic and that the activational state of these “elements” can be monitored by the expression of the mRNA for activity-regulated cytoskeletal protein (ARC). Finally we apply these ideas to analyze recent data examining ARC expression during contextual fear conditioning and find that there are indeed many similarities between stimulus elements and amygdala neurons. The data also suggest some revisions in the conceptualization of how the population of stimulus elements is sampled from

The Mechanisms of Fear Sensitization Caused by Acute Traumatic Stress: from Induction to Expression to Long-Lasting Reversal

Fear is an adaptive response that is normally proportional to the level of imposed threat, which allows for a balance between defensive behavior and other behaviors necessary for survival. However, fear becomes maladaptive when the level is inappropriate to the level of imposed threat. Exposure to a severe stressor can alter future fear learning to become disproportionate to the actual level of threat, potentially leading to generalized fear to less threatening circumstances (Rau, DeCola, and Fanselow, 2005). Inappropriate fear regulation after severe stress is a hallmark of post-traumatic stress disorder (PTSD). The primary goal of the experiments in this dissertation is to investigate the biological mechanisms that underlie both induction and expression of stress-enhanced fear learning (SEFL), a model developed and tested in rats to demonstrate that an acute footshock stressor nonassociatively and permanently enhances conditional fear learning.In the SEFL procedure, rats are given 15 unsignaled footshocks in a certain context, and some time later, are given a single footshock in a novel context. When rats are tested for changes in freezing levels in the novel context in absence of a shock, they show exaggerated levels of freezing behavior, which is called SEFL. Many features of SEFL are similar to the symptoms of PTSD. Experiments in Chapter 1 of this dissertation show that corticosterone (CORT) is necessary to induce SEFL. This effect is demonstrated using intraperitoneal injections of metyrapone, a CORT synthesis blocker. Metyrapone before, but not after the 15 shocks dose-dependently attenuated SEFL and plasma CORT levels during the 15-shock stressor. Moreover, it is shown that the basolateral amygdala (BLA) must be functional during, but not after the 15-shock stressor. A glucocorticoid receptor (GR) antagonist infused into the BLA also attenuated SEFL; so, CORT acting on GRs in the BLA is necessary to induce SEFL.Further work in Chapter 2 explored the mechanisms underlying expression of SEFL. CORT drove long-term alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR) subunit glutamate receptor 1 (GluA1), expression in the BLA, but not GluA2, or the glutamate N-methyl-D aspartate receptor (NMDAR) subunit GluN1. Infusing an AMPAR antagonist into the BLA after the severe stressor temporarily prevented sensitized fear expression. Experiments in Chapter 3 targeted GluA1 synthesis in the BLA using antisense oligonucleotide (ASO) treatments post-stress, which surprisingly reversed SEFL long-term. The most interesting finding in this set of experiments was that reversal of SEFL by ASO treatment did not prevent fear learning or amygdala function, nor did it affect associative fear to the stressor context. Moreover, in Chapter 3 we examined the functional importance of increased GluA1 in the BLA after SEFL. This was accomplished with post-stressor intra-BLA infusions of a GluA2-lacking AMPAR blocker, IEM-1460, which reduced SEFL. In conclusion, these results elucidate novel neurobiological mechanisms underlying sensitized behavioral responses observed using the SEFL model in rats, with potential relevance to PTSD treatments in humans. Specifically, the collective findings show that that CORT acts on GRs in the BLA during the stressor to upregulate the GluA1 subunit of the AMPAR long-term, which elucidates novel mechanisms for the induction and the expression of SEFL. Furthermore, the finding that a single ASO treatment directed at the AMPARs within the BLA restored normal fear responding is especially relevant for developing novel and potentially more effective treatments for PTSD. Clinical implications are discussed throughout the present work

Neurobehavioral perspectives on the distinction between fear and anxiety.

In this review, we discuss the usefulness of the distinction between fear and anxiety. The clinical use of the labels is ambiguous, often defining one in terms of the other. We first consider what a useful, objective, and scientifically valid definition would entail and then evaluate several fear/anxiety distinctions that have been made in the neurobiological literature. A strong distinction should specify the difference in conditions that lead to fear versus anxiety. Additionally, fear and anxiety should generate distinct sets of behaviors. Ideally, the two states should be supported by distinguishable neuroanatomical circuits. Such a conceptualization would be consistent with the National Institute of Mental Health's Research Domain Criteria (RDoc). The majority of neurobiological approaches to the fear versus anxiety distinction fail to differentiate the two states in terms of behavior, often using the exact same behavioral measures as indicators. Of the two that do, only Predatory Imminence Theory provides a distinction both in terms of cause and effect. Indeed, that approach provides a ready distinction of anxiety, fear, and panic in terms of both antecedent conditions and response selection rules. Additionally, it appeals to distinct neural circuits to generate these modes of action

Neurobehavioral perspectives on the distinction between fear and anxiety

In this review, we discuss the usefulness of the distinction between fear and anxiety. The clinical use of the labels is ambiguous, often defining one in terms of the other. We first consider what a useful, objective, and scientifically valid definition would entail and then evaluate several fear/anxiety distinctions that have been made in the neurobiological literature. A strong distinction should specify the difference in conditions that lead to fear versus anxiety. Additionally, fear and anxiety should generate distinct sets of behaviors. Ideally, the two states should be supported by distinguishable neuroanatomical circuits. Such a conceptualization would be consistent with the National Institute of Mental Health's Research Domain Criteria (RDoc). The majority of neurobiological approaches to the fear versus anxiety distinction fail to differentiate the two states in terms of behavior, often using the exact same behavioral measures as indicators. Of the two that do, only Predatory Imminence Theory provides a distinction both in terms of cause and effect. Indeed, that approach provides a ready distinction of anxiety, fear, and panic in terms of both antecedent conditions and response selection rules. Additionally, it appeals to distinct neural circuits to generate these modes of action

Isomorphisms between psychological processes and neural mechanisms: from stimulus elements to genetic markers of activity.

Traditional learning theory has developed models that can accurately predict and describe the course of learned behavior. These "psychological process" models rely on hypothetical constructs that are usually thought to be not directly measurable or manipulable. Recently, and mostly in parallel, the neural mechanisms underlying learning have been fairly well elucidated. The argument in this essay is that we can successfully uncover isomorphisms between process and mechanism and that this effort will help advance our theories about both processes and mechanisms. We start with a brief review of error-correction circuits as a successful example. Then we turn to the concept of stimulus elements, where the conditional stimulus is hypothesized to be constructed of a multitude of elements only some of which are sampled during any given experience. We discuss such elements with respect to how they explain acquisition of associative strength as an incremental process. Then we propose that for fear conditioning, stimulus elements and basolateral amygdala projection neurons are isomorphic and that the activational state of these "elements" can be monitored by the expression of the mRNA for activity-regulated cytoskeletal protein (ARC). Finally we apply these ideas to analyze recent data examining ARC expression during contextual fear conditioning and find that there are indeed many similarities between stimulus elements and amygdala neurons. The data also suggest some revisions in the conceptualization of how the population of stimulus elements is sampled from

Induction and Expression of Fear Sensitization Caused by Acute Traumatic Stress.

Fear promotes adaptive responses to threats. However, when the level of fear is not proportional to the level of threat, maladaptive fear-related behaviors characteristic of anxiety disorders result. Post-traumatic stress disorder develops in response to a traumatic event, and patients often show sensitized reactions to mild stressors associated with the trauma. Stress-enhanced fear learning (SEFL) is a rodent model of this sensitized responding, in which exposure to a 15-shock stressor nonassociatively enhances subsequent fear conditioning training with only a single trial. We examined the role of corticosterone (CORT) in SEFL. Administration of the CORT synthesis blocker metyrapone prior to the stressor, but not at time points after, attenuated SEFL. Moreover, CORT co-administered with metyrapone rescued SEFL. However, CORT alone without the stressor was not sufficient to produce SEFL. In these same animals, we then looked for correlates of SEFL in terms of changes in excitatory receptor expression. Western blot analysis of the basolateral amygdala (BLA) revealed an increase in the GluA1 AMPA receptor subunit that correlated with SEFL. Thus, CORT is permissive to trauma-induced changes in BLA function