Investigating the acute role of corticotrophin releasing factor in visual cortical circuits and visual

The ability to respond to environmental threats is critical for survival, and activation of the body’s stress-response signaling pathways is fundamentally adaptive. However, excessive stress accumulation can lead to neuropsychiatric illness such as generalized anxiety, depression, and post-traumatic stress disorder (PTSD). Disturbances in visual function and processing are common in PTSD and anxiety-related conditions; alterations in structure and function of visual cortex are reported widely in clinical and pre-clinical investigations. Studies of such conditions have focused primarily on the limbic-hypothalamic circuitry that mediates the stress response and threat learning/memory, with less attention paid to the visual cortical circuitry critical for sensory perception of threatening/aversive stimuli, key to the function of those stress processes. Our limited understanding of the functional links between stress signaling and visual circuitry thus represents a crucial knowledge gap in the field. Signaling through stress-related neuropeptide corticotrophin releasing factor (CRF) and its receptor (CRFR1) in visual cortical circuits provides a potential
mechanism that links affective/stressful experience to acute and chronic changes in visual function. Cortical CRFexpressing cells are a sub-type of vasoactive intestinal peptide (VIP) inhibitory interneurons, that disinhibit local circuits in the primary visual cortex (V1), altering visual processing in response to attention and context. Our central hypothesis is that these V1CRF cells are activated by aversive stimuli, disinhibiting and exciting L2/3 pyramidal neurons synergistically through synaptic disinhibition and CRF neuromodulation, altering visual processing as needed during a stressful experience. The objectives of this proposal are to determine how V1CRF neurons are integrated into cortical circuits in primary visual cortex (V1), how V1CRF neurons respond to both affective and visual stimulation, and how V1CRF activity and CRF/CRFR1 signaling alter circuit function and visual processing. Using whole-cell electrophysiology, we will identify the distinct properties of V1CRF neurons and their efferent connectivity to excitatory and inhibitory neurons in V1, and determine how CRF/CRFR1 signaling alters pyramidal cell activity and output. Multiplexed fluorescence confocal imaging will reveal the spatial relationship between V1CRF terminals and CRFR1-positive dendritic spines on L2/3 pyramidal neurons. Using in vivo two-photon imaging, we will determine the visual responsivity and tuning properties of V1CRF neurons, whether their inhibition impairs gain and visual processing in pyramidal neurons, and how CRFR1 activation enhances principal cell responses to visual stimulation. Finally, we will use in vivo fiber photometry to understand how V1CRF neurons and V1 pyramidal neurons respond to affective stimuli of negative and positive valences. These studies will provide novel physiological information about how V1CRF neurons respond to stressful stimuli and influence sensory processing, reveal the influence of CRF peptidergic signaling on fundamental aspects of visual processing, and provide the foundation for future R01-level proposals investigating adaptive and dysregulated affective visual circuitry.

Grant Number: 5P20GM144230-05
NIH Institute/Center: NIH
Principal Investigator: Morgan Bridi