Corticotropin-Releasing Factor (CRF) circuit modulation of cognition and motivation

Abstract

The neuropeptide, corticotropin-releasing factor (CRF), is a key modulator of physiological, endocrine, and behavioral responses during stress. Dysfunction of the CRF system has been observed in stress-related affective disorders including post-traumatic stress disorder, depression, and anxiety. Beyond affective symptoms, these disorders are also characterized by impaired cognition, for which current pharmacological treatments are lacking. Thus, there is a need for pro-cognitive treatments to improve quality of life for individuals suffering from mental illness. In this review, we highlight research demonstrating that CRF elicits potent modulatory effects on higher-order cognition via actions within the prefrontal cortex and subcortical monoaminergic and cholinergic systems. Additionally, we identify questions for future preclinical research on this topic, such as the need to investigate sex differences in the cognitive and microcircuit actions of CRF, and whether CRF may represent a pharmacological target to treat cognitive dysfunction. Addressing these questions will provide new insight into pathophysiology underlying cognitive dysfunction and may lead to improved treatments for neuropsychiatric disorders.

Keywords: Acetylcholine; Basal forebrain; Cognitive flexibility; Corticotropin-releasing factor (CRF); Cost/benefit decision-making; Dopamine (DA); Dorsal raphe nucleus (DR); Effort-related choice; Locus coeruleus (LC); Medial septum (MS); Motivation; Norepinephrine (NE); Nucleus; Object location memory; Prefrontal cortex (PFC); Serotonin (5-HT); Sex differences; Sustained attention; Ventral tegmental area (VTA); Working memory; accumbens (NAc).

Figure 1.. CRF acts on the LC-NE and DR-5-HT systems to modulate cognitive flexibility.

A. In unstressed male rats, low doses of intra-LC CRF that produce moderate increases in LC activity improve EDS performance in an attentional set shifting task. Higher concentrations that produce a maximal increase LC activity have no effect on EDS but improve reversal learning (REV). Although this has not been tested in females, evidence for a shift to the left in the CRF dose-response curve for LC activation in females (gray) compared to males (black) suggests that the dose-response for intra-LC CRF effects on cognitive function would be shifted in a similar manner. B. In unstressed male rats, low doses of CRF infused into the DR inhibit 5-HT neuronal activity via actions at CRF1 receptors while CRF2-selective agonists have no effects. This is associated with improved performance in an operant strategy shifting task. Following stress exposure, CRF2 receptors are recruited to the plasma membrane in the DR and CRF elicits excitatory effects on 5-HT neuronal activity in animals that exhibit a proactive coping strategy. These actions are associated with enhancement of REV.

Figure 2.. CRF1 receptor activity in the MS impairs spatial memory.

Local infusions of CRF into the MS impair hippocampal-dependent object location memory. Male rats are more sensitive to these actions, such that a low CRF dose that is impairing in males has no effect in females. Compared to males, female rats have greater MS expression levels of CRF-binding protein (CRF-bp), which sequesters CRF and limits its bioavailability. Increased levels of CRF-bp in females could reduce the behavioral and physiological effects of CRF and may account for their decreased sensitivity to the behavioral actions of CRF transmission in the MS. However, causal manipulations demonstrating that the sex difference in CRF-bp fully accounts for the sex difference in behavior still need to be completed.

Figure 3.. CRF1 signaling in the caudal dmPFC impairs working memory.

In male rats, local PFC CRF release and subsequent activation of CRF1 receptors coupled to PKA impairs performance in a delayed alternation test of spatial working memory. These actions are associated with a robust degradation in delay-related activity of PFC pyramidal neurons in animals undergoing working memory testing.

Figure 4.. Schematic of rodent brain depicting distribution of CRF cell bodies and receptor subtypes known to modulate cognition.

Areas discussed in this review include the prefrontal cortex (PFC), medial septum (MS), dorsal raphe (DR) nucleus, ventral tegmental area (VTA), and locus coeruleus (LC). It is unknown whether CRF acts via CRF1, CRF2, or both receptor subtypes in the VTA to modulate effort-related choice. Moreover, although evidence suggests CRF may also act within the nucleus accumbens (NAc) to modulate effort-related choice, this hypothesis remains to be explicitly tested.