Correlates of motivation and reward

National Institute On Drug Abuse

Investigators

Linked publications, trials & patents

Abstract

I am summarizing the findings of two ongoing projects: Project 1: Role of Parabrachial Nucleus in Opioid Withdrawal Opioid withdrawal leads to negative emotional symptoms, but the underlying neural mechanisms are not well understood. Previous studies show that during opioid withdrawal, the central nucleus of the amygdala (CEA), particularly its capsular part (CeC), becomes highly active. This raises questions about the brain regions that might activate CeC during opioid withdrawal. One candidate is the parabrachial nucleus (PBN), which has glutamatergic neurons, including calcitonin gene-related peptide (CGRP) neurons in the external lateral PBN (elPBN). These CGRP-expressing neurons project to the CeC and are implicated in pain-related negative emotions and fear memory. Additionally, PBN has a high expression of mu opioid receptors (MOR). The hypothesis is that during opioid withdrawal, a subgroup of PBN neurons becomes active, and the CeC-projecting elPBN CGRP-expressing neurons contribute to CeC activation. To study PBN neuron activity during opioid withdrawal, c-Fos, a marker of cellular activation, was examined in the PBN after inducing opioid withdrawal in mice using morphine and naloxone. The elPBN area showed significantly increased c-Fos expression compared to controls, and many activated elPBN neurons co-expressed MOR and CGRP mRNA. Moreover, differences in c-Fos-expressing neurons were observed in the lateral superior subdivisions of the PBN in naloxone-treated mice. Silencing glutamatergic PBN neurons using chemogenetic procedures reduced CeC activation and withdrawal symptoms including aversive effects in mice, indicating the role of PBN in opioid withdrawal. These findings suggest that PBN afferents are critical for CeC activation during withdrawal and contribute to aversive effects. Future studies will explore more specific neural populations in the PBN, including MOR- and CGRP-expressing neurons. Project 2: Functions of Supramammillary Neurons Projecting to the Lateral Preoptic Area The lateral preoptic area (LPO) projects strongly to the lateral habenular nucleus (LHb), associated with negative reward prediction errors and aversive effects. LPO receives inputs from the septohippocampal system, medial prefrontal cortex (MPFC), and the supramammillary region (SuM). This suggests that LPO conveys environment-dependent approach and avoidance responses to LHb. The influence of SuM inputs on LPO processes was studied. SuM sends efferents to LPO and other regions, receiving inputs from pontine structures, septohippocampal structures, and MPFC, among others. Notably, SuM transfers information from pontine structures to LPO. Optogenetic stimulation of SuM-LPO glutamatergic neurons was found to produce positive reinforcement. With an intracranial self-stimulation test, mice learned to activate SuM-LPO neurons, promoting operant approach behavior. Calcium fiber-photometry test showed that these neurons responded to positive and negative stimuli. Water and its cue decreased their activity, while footshock and its cue increased it. Salient sensory stimuli like bright light and loud noise also increased their activity. SuM-LPO GluN likely respond to uncertain and attention-demanding stimuli, facilitating investigatory behavior under stressful or uncertain conditions. Water and its cue might decrease activity because their activation promotes investigatory behavior rather than consumption. Further studies will validate these hypotheses.