Biology subjects

Ingebretson, A. E.

Publications and source records attributed to Ingebretson, A. E..

4 recordsLinked to original sources

bioRxiv2024

Cholinergic interneurons in the nucleus accumbens are a site of cellular convergence for corticotropin release factor and estrogen regulation

Cholinergic interneurons (ChIs) act as master regulators of striatal output, finely tuning neurotransmission to control motivated behaviors. ChIs are a cellular target of many peptide and hormonal neuromodulators, including corticotropin releasing factor, opioids, insulin and leptin, which can influence an animals behavior by signaling stress, pleasure, pain and nutritional status. However, little is known about how sex hormones via estrogen receptors influence the function of these other neuromodulators. Here, we performed in situ hybridization on mouse striatal tissue to characterize the effect of sex and sex hormones on choline acetyltransferase (Chat), estrogen receptor alpha (Esr1), and corticotropin releasing factor type 1 receptor (Crhr1) expression. Although we did not detect sex differences in ChAT protein levels in the striatum, we found that female mice have more Chat mRNA-expressing neurons than males. At the population level, we observed a sexually dimorphic distribution of Esr1- and Crhr1-expressing ChIs in the ventral striatum that demonstrates an antagonistic correlational relationship, which is abolished by ovariectomy. Only in the NAc did we find a significant population of ChIs that co-express Crhr1 and Esr1. At the cellular level, Crhr1 and Esr1 transcript levels were negatively correlated only during estrus, indicating that changes in sex hormones levels can modulate the interaction between Crhr1 and Esr1 mRNA levels. Together, these data provide evidence for the unique expression and interaction of Esr1 and Crhr1 in ventral striatal ChIs, warranting further investigation into how these transcriptomic patterns might underlie important functions for ChIs at the intersection of stress and reproductive behaviors.

neuroscience↗

bioRxiv2023

CRF release from a unique subpopulation of accumbal neurons constrains action-outcome acquisition in reward learning

BackgroundThe nucleus accumbens (NAc) mediates reward learning and motivation. Despite an abundance of neuropeptides, peptidergic neurotransmission from the NAc has not been integrated into current models of reward learning. The existence of a sparse population of neurons containing corticotropin releasing factor (CRF) has been previously documented. Here we provide a comprehensive analysis of their identity and functional role in shaping reward learning. MethodsTo do this, we took a multidisciplinary approach that included florescent in situ hybridization (Nmice [≥] 3), tract tracing (Nmice = 5), ex vivo electrophysiology (Ncells [≥] 30), in vivo calcium imaging with fiber photometry (Nmice [≥] 4) and use of viral strategies in transgenic lines to selectively delete CRF peptide from NAc neurons (Nmice [≥] 4). Behaviors used were instrumental learning, sucrose preference and spontaneous exploration in an open field. ResultsHere we show that the vast majority of NAc CRF-containing (NAcCRF) neurons are spiny projection neurons (SPNs) comprised of dopamine D1-, D2- or D1/D2-containing SPNs that primarily project and connect to the ventral pallidum and to a lesser extent the ventral midbrain. As a population, they display mature and immature SPN firing properties. We demonstrate that NAcCRF neurons track reward outcomes during operant reward learning and that CRF release from these neurons acts to constrain initial acquisition of action-outcome learning, and at the same time facilitates flexibility in the face of changing contingencies. ConclusionWe conclude that CRF release from this sparse population of SPNs is critical for reward learning under normal conditions.

neuroscience↗

bioRxiv2023

Corticotropin releasing factor alters the functional diversity of accumbal cholinergic interneurons

Cholinergic interneurons (ChIs) provide the main source of acetylcholine in the striatum and have emerged as a critical modulator of behavioral flexibility, motivation, and associative learning. In the dorsal striatum, ChIs display heterogeneous firing patterns. Here, we investigated the spontaneous firing patterns of ChIs in the nucleus accumbens (NAc) shell, a region of the ventral striatum. We identified four distinct ChI firing signatures: regular single-spiking, irregular single-spiking, rhythmic bursting, and a mixed-mode pattern composed of bursting activity and regular single spiking. ChIs from females had lower firing rates compared to males and had both a higher proportion of mixed-mode firing patterns and a lower proportion of regular single-spiking neurons compared to males. We further observed that across the estrous cycle, the diestrus phase was characterized by higher proportions of irregular ChI firing patterns compared to other phases. Using pooled data from males and females, we examined how the stress-associated neuropeptide corticotropin releasing factor (CRF) impacts these firing patterns. ChI firing patterns showed differential sensitivity to CRF. This translated into differential ChI sensitivity to CRF across the estrous cycle. Furthermore, CRF shifted the proportion of ChI firing patterns toward more regular spiking activity over bursting patterns. Finally, we found that repeated stressor exposure altered ChI firing patterns and sensitivity to CRF in the NAc core, but not the NAc shell. These findings highlight the heterogeneous nature of ChI firing patterns, which may have implications for accumbal-dependent motivated behaviors. New and NoteworthyChIs within the dorsal and ventral striatum can exert a huge influence on network output and motivated behaviors. However, the firing patterns and neuromodulation of ChIs within the ventral striatum, specifically the NAc shell, are understudied. Here we report that NAc shell ChIs have heterogenous ChI firing patterns that are labile and can be modulated by the stress-linked neuropeptide CRF and by the estrous cycle.

neuroscience↗

bioRxiv2018

Cholinergic interneurons as a novel target of CRF in the striatum that is spared by repeated stress

Acute stressors can stimulate appetitive and exploratory behaviors, not just produce negative affect that impair performance. Corticotropin releasing factor (CRF), which is released in the brain in response to stress, acts on different targets and circuits to mediate both the negative and positive effects of stress. In the nucleus accumbens, CRF facilitates appetitive behavior through mechanisms not fully understood. Here we report that cholinergic interneurons (CINs) are a novel target for CRF actions in the striatum. CRF enhances the spontaneous firing via activation of CRF-type 1 receptors expressed on CINs. This causes the activation muscarinic acetylcholine receptors type 5, which mediate CRF potentiation of dopamine transmission in the striatum. Repeated stress selectively dampens some CRF functions but spare effect on CINs and changes CRF-R1 expression in a cell-specific manner. These data highlight the existence of diverse CRF targets within the striatum, which vary in their resilience to stress.

neuroscience↗