Dissecting the Roles of GABA and Neuropeptides from Rat Central Amygdala CRF Neurons in Anxiety and Fear Learning

Abstract

Graphical AbstractHighlights d Central amygdala CRF neurons release GABA and several neuropeptides d Preventing GABA release in these neurons suppresses basal anxiety-like behavior d Knockdown of CRF or dynorphin prevents anxiety evoked by chemogenetic activation d CRF or dynorphin knockdown reduces but neurotensin knockdown enhances fear learning SUMMARY Central amygdala (CeA) neurons that produce corticotropin-releasing factor (CRF) regulate anxiety and fear learning. These CeA CRF neurons release GABA and several neuropeptides predicted to play important yet opposing roles in these behaviors. We dissected the relative roles of GABA, CRF, dynorphin, and neurotensin in CeA CRF neurons in anxiety and fear learning by disrupting their expression using RNAi in male rats. GABA, but not CRF, dynorphin, or neurotensin, regulates baseline anxiety-like behavior. In contrast, chemogenetic stimulation of CeA CRF neurons evokes anxiety-like behavior dependent on CRF and dynorphin, but not neurotensin. Finally, knockdown of CRF and dynorphin impairs fear learning, whereas knockdown of neurotensin enhances it. Our results demonstrate distinct behavioral roles for GABA, CRF, dynorphin, and neurotensin in a subpopulation of CeA neurons. These results highlight the importance of considering the repertoire of signaling molecules released from a given neuronal population when studying the circuit basis of behavior.

Kappa opioid receptors in the central amygdala modulate spinal nociceptive processing through an action on amygdala CRF neurons

“…Evidence for functional links between amygdala KOR and CRF systems [38] let us to explore the contribution of CRF neurons to the descending modulation of nociceptive processing. CRF neurons in the CeA project to extra-amygdalar targets to promote averse-affective behaviors [39,41,[67][68][69]. Amygdala CRF functions are under tonic inhibitory control of KOR as shown with a KOR antagonist that enhanced the synaptic effects of CRF on medial CeA neurons [70].…”

“…Male, hemizygous transgenic and wildtype Crh-Cre rats on Wistar background [39][40][41] (initial breeding pairs kindly provided by Dr. Robert Messing, UT Austin), 250-350 g at time of testing, were housed on a 12-h light-dark cycle with unrestricted access to food and water. On the day of the experiment, animals were acclimated to the laboratory for at least 1 h. All procedures were approved by the Institutional Animal Care and Use Committee (IACUC) at the Texas Tech University Health Sciences Center (TTUHSC) and conformed to the policies and recommendations of the National Institutes of Health (NIH) Guide for the Care and Use of Laboratory Animals.…”

Co-released Norepinephrine and Galanin Act on Different Timescales to Promote Stress-Induced Anxiety-Like Behavior

“…More broadly, our results may also shed light on how other small molecule and peptide co-transmitter systems function throughout the nervous system. Although some of the complexity created by co-transmission has been dissected with the aid of modern neuroscience techniques, such as using RNAi to knockdown individual co-transmitters in a single cell type (43), this remains an understudied area of research and there is much to discover about the functional effects of co-released neurotransmitters. Our findings on the differential roles of NE and galanin in the LC-NE system point to the importance of examining the roles of co-transmitters over different timescales and may be applicable to other neuromodulatory systems that co-express neuropeptides, such as the serotonergic dorsal raphe neurons which express neuropeptide Y and galanin in some species, or the dopaminergic ventral tegmental area neurons which express high levels of brain-derived neurotrophic factor (44,45).…”

A conserved neuropeptide system links head and body motor circuits to enable adaptive behavior

“…Disruptions in neuromodulatory transmitter systems are associated with a variety of behavioral and neuropsychiatric conditions, including eating disorders, anxiety, stress and mood disorders, depression, and schizophrenia. [1][2][3] To achieve their effects, neuromodulatory systems may act broadly through projections across many brain regions, or have circuit-specific actions based on the GPCRs involved and their cellular expression. A single neuromodulator may therefore perform vastly different signaling functions across the circuits where it is released.…”