# Parvalbumin Interneuron Regulation of a Prelimbic to Ventrolateral Periaqueductal Gray Pathway for Modulating Pain Following Adolescent Intermittent Ethanol Exposure

> **NIH NIH K99** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2024 · $194,551

## Abstract

PROJECT SUMMARY
Adolescent alcohol misuse is a significant risk factor for alcohol use disorder in adulthood. Particularly
concerning are the long-term effects on brain maturation and associated cognitive function, including the ability
to appropriately process and respond to pain. A growing body of research indicates that adolescent alcohol
misuse enhances pain sensitivity and anxiety in adulthood, and increased pain sensitivity and heightened
anxiety may increase the risk for alcohol misuse later in life. Recently, a role for a circuit involving the
basolateral amygdala (BLA), prelimbic (PrL) cortex, and ventrolateral periaqueductal gray (vlPAG) in pain
processing has been described. Within this circuit, activation of the BLA by nociceptive stimuli results in
increased feedforward inhibition of PrL neurons projecting to the vlPAG (PrLPAG). This feedforward inhibition is
mediated by parvalbumin interneurons (PVINs) in the PrL. Within this circuit, PVINs modulate pain sensitivity
and pain-related affect by regulating the activity of PrLPAG neurons. Adolescence is a critical period for
development. Environmental insults occurring during adolescence, such as those caused by repeated
episodes of binge-like alcohol consumption, disrupt normal development of PrL circuitry. These changes
include reduced intrinsic excitability of and evoked AMPA and NMDA mediated currents onto PVINs. In
addition, preliminary data we have collected indicates that following adolescent intermittent alcohol exposure
the excitatory/inhibitory (E/I) balance evoked by optogenetic stimulation of BLA terminals in the PrL cortex is
reduced at PrL PVINs and increased at PrLPAG neurons. Further, following alcohol exposure during
adolescence, the density of perineuronal nets (PNNs) which enwrap PVINs and restrict plasticity is increased
in the PrL. The overarching hypothesis of this proposal is that persistent changes in synaptic function following
AIE are associated with altered activation patterns of PrL PVINs and PrLPAG neurons that are correlated with
altered pain sensitivity. We further hypothesize that digestion of PNNs using chondroitinase ABC will reverse
changes in the E/I balance at PrL PVINs and PrLPAG neurons. The proposed studies will use a combination of
cell-type and projection specific chemogenetic manipulations to determine the effect of changes in the activity
of PrL PVINs and PrLPAG neurons on nociception and pain-related affect following adolescent alcohol exposure.
Changes in the activation patterns of PrL PVINs and PrLPAG neurons in response to nociceptive stimuli will also
be assessed using fiber photometry. Finally, to determine whether PNNs stabilize altered synaptic function
following adolescent alcohol exposure, PNNs will be digested and the E/I balance at BLA inputs onto PVINs
and PrLPAG neurons will be measured using acute slice electrophysiology. These experiments will provide
valuable insights into how changes in PrL PVIN and PrLPAG synaptic function r...

## Key facts

- **NIH application ID:** 10948941
- **Project number:** 1K99AA031717-01
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** James Daniel Obray
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $194,551
- **Award type:** 1
- **Project period:** 2024-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10948941

## Citation

> US National Institutes of Health, RePORTER application 10948941, Parvalbumin Interneuron Regulation of a Prelimbic to Ventrolateral Periaqueductal Gray Pathway for Modulating Pain Following Adolescent Intermittent Ethanol Exposure (1K99AA031717-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10948941. Licensed CC0.

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