Access to highly palatable and calorically dense foods contributes to increasing rates of obesity worldwide. Some have made the controversial argument that consumption of such foods can lead to "food addiction," yet little is known about how long-term access to highly palatable foods might alter goal-directed learning and decision making. In the following experiments, rats were given 5 weeks of continuous or restricted daily access to sweetened condensed milk (SCM) before instrumental training for food reward. Subsequently we examined whether goal-directed performance was impaired in these groups using the outcome-devaluation task. Control rats reduced responding following devaluation of the earned outcome as did those with previous continuous access to SCM. Of interest, rats with previous restricted access to SCM responded similarly under the devalued and nondevalued conditions, indicating loss of goal-directed control of responding. To identify whether the loss of goal-directed control was accompanied by differences in neuronal activity, we used c-Fos immunohistochemistry to examine the patterns of activation during devaluation testing. We observed greater c-Fos immunoreactivity in the dorsolateral striatum (DLS) and associated cortical regions in the group that received previous restricted access to SCM and demonstrated a lack of sensitivity to outcome devaluation. Infusion of the AMPA-receptor antagonist CNQX or dopamine D1-receptor antagonist SCH-23390 into the DLS before testing restored goal-directed performance in the restricted SCM group, confirming that this region is essential for habit-based performance. These results indicate that previous diet can alter subsequent learning and activity in the neural circuits that support performance.

Hypocretin/orexin has a well-established role in wakefulness and in the maintenance of arousal. Because stress is associated with arousal, it has been proposed that hypocretin is also involved in stress. However, it is not clear if this is true for all forms of stress. To clarify this issue, we compared four conditions combining high arousal with no or low stress (wakefulness and exploration) or high stress (contextual fear and restraint) in the rat. We looked at Fos expression in hypocretin neurons, hypocretin-1 levels in cerebrospinal fluid and cardiovascular and behavioural changes after pharmacological blockade with the dual hypocretin receptor antagonist, almorexant. Fos expression in hypocretin neurons was highest with wakefulness and exploration, also high with fear but not significant with restraint. Hypocretin-1 levels were consistent with this pattern, although the differences were not as marked. Hypocretin receptor blockade with almorexant reduced the pressor, tachycardic and locomotor responses of wakefulness and exploration as well as the pressor and sympathetic component of the tachycardic response of fear. In contrast, almorexant did not reduce the pressor and tachycardic responses of restraint and nor did it reduce the pressor, tachycardic and locomotor responses of another stressor, i.e. cold exposure. Thus, hypocretin is not involved in all forms of stress. Comparison of the different conditions suggests that, regardless of stress, hypocretin involvement occurs when the arousal associated with the response includes increased attention to environmental cues. When it does, hypocretin will at least contribute to the cardiovascular response. The findings are of clinical relevance to some forms of psychological stress.

No abstract

The nucleus accumbens shell (AcbSh) is required to inhibit drug seeking after extinction training. Conversely, the lateral hypothalamus (LH), which receives projections from AcbSh, mediates reinstatement of previously extinguished drug seeking. We hypothesized that reversible inactivation of AcbSh using GABA agonists (baclofen/muscimol) would reinstate extinguished alcohol seeking and increase neuronal activation in LH. Rats underwent self-administration training for 4% (v/v) alcoholic beer followed by extinction. AcbSh inactivation reinstated extinguished alcohol seeking when infusions were made after, but not before, extinction training. We then used immunohistochemical detection of c-Fos as a marker of neuronal activity, combined with immunohistochemical detection of the orexin and cocaine-and amphetamine-related transcript (CART) peptides, to study the profile and phenotype of neural activation during reinstatement produced by AcbSh inactivation. AcbSh inactivation increased c-Fos expression in hypothalamus, as well as in paraventricular thalamus and amygdala. Within hypothalamus, there was an increase in the number of orexin and CART cells expressing c-Fos. Finally, we hypothesized that concurrent inactivation of LH would prevent reinstatement produced by inactivation of AcbSh alone. Our results confirmed this. Together, these findings suggest that AcbSh mediates extinction of reward seeking by inhibiting hypothalamic neuropeptide neurons. Reversible inactivation of the AcbSh removes this influence, thereby releasing hypothalamus from AcbSh inhibition and enabling reinstatement of reward seeking. These ventral striatal-hypothalamic circuits for extinction overlap with those that mediate satiety, and we suggest that extinction training inhibits drug seeking because it co-opts neural circuits originally selected to produce satiety.

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.

Rats were shocked in a context and then exposed to that context in the absence of shock. Shorter intervals between these extinction trials produced more long-term freezing than did longer ones, and shorter intervals between the final extinction trial and test produced more freezing than did longer ones. A short interval between a context extinction trial and test with an extinguished conditioned stimulus (CS) produced more freezing than did a longer one, and a short interval between a nonreinforced context exposure and an extinguished CS reinstated freezing when the CS was tested 24 hr later. The results suggest that recent fear acts to favor subsequent retrieval of the memory formed at conditioning rather than extinction and to render the retrieved memory more salient.

Pavlovian fear conditioning depends on prediction error, or the discrepancy between actual and expected outcomes. We used immunohistochemistry, neuronal tract tracing, and reversible inactivation to study the role of prefrontal cortex and thalamocortical pathways in predictive fear learning. Unexpected, but not expected, conditioned stimulus (CS)-unconditioned stimulus (US) presentations caused increased c-Fos expression in the prefrontal cortex (PFC), midline thalamus, lateral amygdala, as well as retrograde labeled midline thalamic afferents to PFC. Reversible inactivation of dorsomedial PFC, but not infralimbic PFC, prevented the associative blocking of fear learning. These results suggest a role for dorsomedial PFC (dmPFC), and a thalamic → dmPFC pathway, in signaling whether or not aversive events are expected or unexpected and so whether they are to be learned about.

Addiction is characterised by a persistent loss of behavioural control resulting in insensitivity to negative feedback and abnormal decision-making. Here we investigated the influence of methamphetamine (METH)-paired contextual cues on decision-making in rats. Choice between goal-directed actions was sensitive to outcome devaluation in a saline-paired context but was impaired in the METH-paired context, a deficit that was also found when negative feedback was provided. Reductions in c-Fos-related immunoreactivity were found in dorsomedial but not dorsolateral striatum after exposure to the METH context suggesting this effect reflected a loss specifically in goal-directed control in the METH context. This reduction in c-Fos was localized to non-enkephalin expressing neurons in the DMS, likely dopamine D1-expressing direct pathway neurons, suggesting a relative change in control by the D1-direct vs. D2-indirect pathways originating in the DMS may have been induced by METH context exposure. To test this suggestion we infused the adenosine 2A receptor antagonist ZM241385 into the dorsomedial striatum prior to test to reduce activity in D2 neurons relative to D1 neurons in the hope of reducing the inhibitory output from this region of the striatum. We found that this treatment fully restored sensitivity to negative feedback in a test conducted in the METH-paired context. These results suggest that drug-exposure alters decision-making by down-regulation of the circuitry mediating goal-directed action, an effect that can be ameliorated by acute A2A receptor inhibition in this circuit.