Abstract
Corticotropin-releasing hormone (CRH) is an essential, evolutionarily-conserved stress neuropeptide. In addition to hypothalamus, CRH is expressed in brain regions including amygdala and hippocampus where it plays crucial roles in modulating the function of circuits underlying emotion and cognition. CRH+ fibers are found in nucleus accumbens (NAc), where CRH modulates reward/motivation behaviors. CRH actions in NAc may vary by the individual's stress history, suggesting roles for CRH in neuroplasticity and adaptation of the reward circuitry. However, the origin and extent of CRH+ inputs to NAc are incompletely understood. We employed viral genetic approaches to map both global and CRH+ projection sources to NAc in mice. We injected into NAc variants of a new designer adeno-associated virus that permits robust retrograde access to NAc-afferent projection neurons. Cre-dependent viruses injected into CRH-Cre mice enabled selective mapping of CRH+ afferents. We employed anterograde AAV1-directed axonal tracing to verify NAc CRH+ fiber projections and established the identity of genetic reporter-labeled cells via validated antisera against native CRH. We quantified the relative contribution of CRH+ neurons to total NAc-directed projections. Combined retrograde and anterograde tracing identified the paraventricular nucleus of the thalamus, bed nucleus of stria terminalis, basolateral amygdala, and medial prefrontal cortex as principal sources of CRH+ projections to NAc. CRH+ NAc afferents were selectively enriched in NAc-projecting brain regions involved in diverse aspects of the sensing, processing and memory of emotionally salient events. These findings suggest multiple, complex potential roles for the molecularly-defined, CRH-dependent circuit in modulation of reward and motivation behaviors.
Highlights
Corticotropin-releasing hormone (CRH) is an essential, evolutionarily conserved neuropeptide that can convey, process, and modulate responses to potential threats (Joëls & Baram, 2009; Vale et al, 1983)
Increased expression of CRH in the central nucleus of the amygdala seems to interfere with the pleasure/reward circuit function, because partial silencing of the augmented expression of the peptide after early-life stress reversed anhedonia in adult rodents (Bolton et al, 2018)
3.1 | The major CRH-expressing afferents to the nucleus accumbens (NAc) originate in the paraventricular nucleus of the thalamus, bed nucleus of the stria terminalis, medial prefrontal cortex, and the basolateral amygdala
Summary
Corticotropin-releasing hormone (CRH) is an essential, evolutionarily conserved neuropeptide that can convey, process, and modulate responses to potential threats (Joëls & Baram, 2009; Vale et al, 1983). CRH-expressing neurons and receptors have been identified throughout selective regions of the brain, where they orchestrate the peptide's influence on numerous brain functions, typically in response to stress or threat (Joëls & Baram, 2009). These seem to reside in tyrosine-hydroxylasepositive axon terminals, a location enabling the peptide to influence dopamine release in the NAc (Lemos et al, 2012) This effect contributes to the modulation of reward and motivation behavior (Lemos et al, 2012). In stress-naïve rodents, microinjections of CRH into the NAc induces a conditioned place preference and increases local dopamine release (Lemos et al, 2012). We used new viral genetic mapping approaches (Oh et al, 2014; Tervo et al, 2016) to uncover the origin and circuitry of NAc-directed CRH+ afferents and compared them with overall sources of input to this nucleus
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