New viral‐genetic mapping uncovers an enrichment of corticotropin‐releasing hormone‐expressing neuronal inputs to the nucleus accumbens from stress‐related brain regions

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.

Striatal Cholinergic Interneurons Are a Novel Target of Corticotropin Releasing Factor

“…In addition, higher density of CRF-containing axonal projections from other brain areas was seen in the NAc compared with the DS. According to both the Allen Brain Atlas as well as a recent study by Itoga et al (2019), the BLA, BNST, and paraventricular nucleus of the thalamus send prominent CRF-containing projections to the NAc, but not the DS (Oh et al, 2014;Itoga et al, 2019). Thus, endogenously released CRF from CRFϩ cells or CRF-containing axonal projections to the NAc is predicted to potentiate ACh-dependent behaviors mediated by the NAc.…”

Corticotropin Releasing Factor Type 1 and 2 Receptor Signaling in the Medial Prefrontal Cortex Modulates Binge-Like Ethanol Consumption in C57BL/6J Mice

“…Previous studies have suggested that alternative sources of mPFC CRF may arise from the brainstem, such as from the CRF-expressing laterodorsal tegmental nucleus of the pons [53]. Recent work has further demonstrated a CRF-positive projection from the mPFC to the nucleus accumbens, suggesting a potential novel source of mPFC CRF distinct from the local interneuron population [54]. Further investigation is needed to determine the precise source of CRF relevant to these present findings.…”

Expression and Distribution of Neuropeptide-Expressing Cells Throughout the Rodent Paraventricular Nucleus of the Thalamus

“…Cells expressing this gene are slightly more dense in the posterior compared to anterior PVT, and expression in both subregions is largely medial and also denser than in the middle antero-posterior subregion of the PVT (Allen Institute, 2004 ). Prior research, in CRH-IRES-Cre mice, had identified considerable numbers of CRH + cells in the PVT (Peng et al, 2017 ), and also reported that they spanned the antero-posterior axis of the PVT, with somewhat higher density in the posterior portion of the PVT (Itoga et al, 2019 ). Using retrograde and anterograde viral tracing, these CRH + cells were found to send a major input to the nucleus accumbens (Itoga et al, 2019 ), although they may project to other regions as well.…”

“…Prior research, in CRH-IRES-Cre mice, had identified considerable numbers of CRH + cells in the PVT (Peng et al, 2017 ), and also reported that they spanned the antero-posterior axis of the PVT, with somewhat higher density in the posterior portion of the PVT (Itoga et al, 2019 ). Using retrograde and anterograde viral tracing, these CRH + cells were found to send a major input to the nucleus accumbens (Itoga et al, 2019 ), although they may project to other regions as well. Despite the generation of a CRH-Cre rat (Pomrenze et al, 2015 ), it remains to be demonstrated that rats also express CRH in the PVT.…”