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

Cholinergic Signaling Alters Stress-Induced Sensitization of Hippocampal Contextual Learning

Post-traumatic stress disorder (PTSD) has a profound contextual component, and has been demonstrated to alter future contextual learning. However, the mechanism by which a single traumatic event affects subsequent contextual experiences has not been isolated. Acetylcholine (ACh) is an important modulator of hippocampus-dependent learning such as contextual memory strength. Using Stress-Enhanced Fear Learning (SEFL), which models aspects of PTSD in rats, we tested whether muscarinic acetylcholine receptors (mAChR) in dorsal hippocampus (DH) are required during trauma for the effect of trauma on subsequent contextual fear learning. We infused scopolamine or vehicle into DH immediately before stress, and tested fear in both the trauma context and a novel context after a mild stressor. The results show that during learning, ACh acting on mAChR within the DH is required for sensitization of future contextual fear learning. However, this effect is selective for contextual learning, as this blockade leaves discrete cue sensitization intact. Rather than simply sensitizing the BLA, as previous studies have suggested, SEFL requires cholinergic signaling in DH for contextual sensitization

Contextual Fear Learning Circuitry and Contributions of Acetylcholine

Learning about context is essential for appropriate behavioral strategies, though pathologically strong contextual memories may form the basis for anxiety disorders such as PTSD. Though the general network of brain regions involved in this learning has been characterized, how neural representations in each region contribute to memory formation and recall, as well as how cholinergic signaling affects normal and maladaptive contextual learning, is not well understood. I used catFISH to compare short-term contextual fear memory reactivation across hippocampus (DH), basolateral amygdala (BLA), prelimbic and infralimbic cortices (mPFC). I found that while DH reactivation is related to contextual processing, BLA reactivation is related to recall of contextual fear memory; mPFC reactivation tracked both contextual and fear information (Ch2). To follow up, I used Fos-Cre mice to tag a contextual fear memory representation in BLA with the inhibitory proton pump ArchT. I then inactivated these memory neurons during a return to the original context, and found that it impaired recall, but that if the memory was first allowed to be recalled, ongoing fear behavior was not disrupted. This effect was similar at both recent and remote time points (Ch2). In order to probe how acetylcholine (ACh) in DH affects contextual processing, I used ChAT-Ai32 mice to selectively activate medial-septal cholinergic inputs to DH with ChR2 during contextual exposure. After pairing the context with shock, mice with enhanced ACh during contextual encoding showed higher levels of fear, suggesting stronger contextual memory formation. I also tested and confirmed the effects of light stimulation using anesthetized recording with choline biosensors (Ch3). As ACh increased the strength of contextual memories, I tested whether it was involved in maladaptive contextual fear in Stress-enhanced fear learning (SEFL), our rat model of sensitization in PTSD. I blocked muscarinic cholinergic signaling in DH or BLA using scopolamine before a traumatic event: 15 unsignaled shocks. I found that this blockade in either brain region not only disrupted fear to the trauma context, but blocked sensitization to a new context normally observed in the model. In DH, though sensitization to new contexts was blocked, sensitization to new tones was intact, suggesting a new role for ACh in DH in controlling contextual sensitization after trauma (Ch4)

Contextual Fear Learning Circuitry and Contributions of Acetylcholine

Learning about context is essential for appropriate behavioral strategies, though pathologically strong contextual memories may form the basis for anxiety disorders such as PTSD. Though the general network of brain regions involved in this learning has been characterized, how neural representations in each region contribute to memory formation and recall, as well as how cholinergic signaling affects normal and maladaptive contextual learning, is not well understood. I used catFISH to compare short-term contextual fear memory reactivation across hippocampus (DH), basolateral amygdala (BLA), prelimbic and infralimbic cortices (mPFC). I found that while DH reactivation is related to contextual processing, BLA reactivation is related to recall of contextual fear memory; mPFC reactivation tracked both contextual and fear information (Ch2). To follow up, I used Fos-Cre mice to tag a contextual fear memory representation in BLA with the inhibitory proton pump ArchT. I then inactivated these memory neurons during a return to the original context, and found that it impaired recall, but that if the memory was first allowed to be recalled, ongoing fear behavior was not disrupted. This effect was similar at both recent and remote time points (Ch2). In order to probe how acetylcholine (ACh) in DH affects contextual processing, I used ChAT-Ai32 mice to selectively activate medial-septal cholinergic inputs to DH with ChR2 during contextual exposure. After pairing the context with shock, mice with enhanced ACh during contextual encoding showed higher levels of fear, suggesting stronger contextual memory formation. I also tested and confirmed the effects of light stimulation using anesthetized recording with choline biosensors (Ch3). As ACh increased the strength of contextual memories, I tested whether it was involved in maladaptive contextual fear in Stress-enhanced fear learning (SEFL), our rat model of sensitization in PTSD. I blocked muscarinic cholinergic signaling in DH or BLA using scopolamine before a traumatic event: 15 unsignaled shocks. I found that this blockade in either brain region not only disrupted fear to the trauma context, but blocked sensitization to a new context normally observed in the model. In DH, though sensitization to new contexts was blocked, sensitization to new tones was intact, suggesting a new role for ACh in DH in controlling contextual sensitization after trauma (Ch4)

Assigning Function to Adult-Born Neurons: A Theoretical Framework for Characterizing Neural Manipulation of Learning.

Neuroscientists are concerned with neural processes or computations, but these may not be directly observable. In the field of learning, a behavioral procedure is observed to lead to performance outcomes, but differing inferences on underlying internal processes can lead to difficulties in interpreting conflicting results. An example of this challenge is how many functions have been attributed to adult-born granule cells in the dentate gyrus. Some of these functions were suggested by computational models of the properties of these neurons, while others were hypothesized after manipulations of adult-born neurons resulted in changes to behavioral metrics. This review seeks to provide a framework, based in learning theory classification of behavioral procedures, of the processes that may be underlying behavioral results after manipulating procedure and observing performance. We propose that this framework can serve to clarify experimental findings on adult-born neurons as well as other classes of neural manipulations and their effects on behavior

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