Medial Dorsal Hypothalamus Mediates the Inhibition of Reward Seeking after Extinction

Abstract

Extinction promotes abstinence from drug seeking. Extinction expression is an active process, dependent on infralimbic prefrontal cortex (ilPFC). However, the neurocircuitry mediating extinction expression is unknown. Here we studied the neural mechanisms for expression of extinction of alcoholic beer seeking in rats. We first examined the pattern of activation in prefrontal cortex projections to medial dorsal hypothalamus (MDH) (i.e., perifornical and dorsomedial nuclei) during extinction expression. Double labeling for retrograde tracer cholera toxin B subunit (CTb) and the neuronal activity marker c-Fos revealed significant recruitment of MDH projecting ilPFC neurons during extinction expression. We then studied the causal role of MDH in inhibiting alcoholic beer seeking during extinction expression. MDH infusion of the inhibitory neuropeptide cocaine-and amphetamine-regulated transcript prevented extinction expression, showing that MDH is necessary for extinction expression. Next we examined the pattern of activation in MDH projections to paraventricular thalamus (PVT) during extinction expression. Double labeling for CTb and c-Fos revealed significant recruitment of PVT projecting MDH neurons during extinction expression. We also showed, using triple-label immunofluorescence, that the majority of PVT projecting extinction neurons express prodynorphin, suggesting that actions at opioid receptors (KORs) in PVT may be critical for inhibiting alcoholic beer seeking. Consistent with this, infusions of a KOR agonist into PVT prevented reinstatement of alcoholic beer seeking showing that PVT KOR activation is sufficient to inhibit alcoholic beer seeking. Together, these findings identify a role for MDH and its ilPFC afferents and PVT efferents in inhibiting alcoholic beer seeking during extinction expression.

Lateral, not medial, prefrontal cortex contributes to punishment and aversive instrumental learning

“…This broad lack of effect on punished responding is consistent with Pelloux et al (2013) finding that neither PL nor IL lesions affected punishment of responding for cocaine. However, it is also somewhat surprising given that PL is implicated in formation of response-outcome associations (Corbit and Balleine 2003;Ostlund and Balleine 2005;Tran-Tu-Yen et al 2009) and the expression of aversive Pavlovian associations (Blum et al 2006;Vidal-Gonzalez et al 2006;Corcoran and Quirk 2007;Sierra-Mercado et al 2011;Lammel et al 2012), whereas IL has been implicated in reductions of instrumental responding following extinction (Peters et al 2008(Peters et al , 2009Marchant et al 2010;Peters and De Vries 2013). Our results suggest that these roles for PL and IL in behavioral control do not extend to aversive instrumental (response-punisher) associations.…”

A unifying model of the role of the infralimbic cortex in extinction and habits

“…As with fear, extinction of alcohol seeking is associated with elevated c-Fos expression in IL (Marchant et al 2010). IL plasticity may also play a role in the extinction of ethanol seeking, as expression of the proplasticity molecule polysialylated neural cell adhesion molecule (PSA-NCAM) is predictive of innate differences in the ability to extinguish ethanol-seeking behavior (Barker et al 2012).…”

“…The IL also projects extensively to the dorsomedial hypothalamus (DMH). Interestingly, the expression of extinction of ethanol seeking has been associated with increased c-Fos expression in IL projections to DMH (Marchant et al 2010). The DMH has previously been associated with motivated behavior, and investigation into control of DMH activity by prefrontal networks is expected to provide considerable information regarding the neurocircuitry of extinction, and potentially how the extinction of alcohol and food seeking differs from cocaine-and fear-motivated learning.…”

The hypothalamus and the neurobiology of drug seeking

“…Recently, we provided evidence that MDH is important for extinction expression, which is defined as the expression of an extinguished reward-seeking response [63]. In this study, rats were initially trained to respond to 4% alcoholic beer.…”