Hippocampal Input to the Nucleus Accumbens Shell Enhances Food Palatability.

BACKGROUND: Insight into the neural basis of hedonic processing has come from studies of food palatability in rodents. Pharmacological manipulations of the nucleus accumbens shell (NAcSh) have repeatedly been demonstrated to increase hedonic taste reactivity, yet the contribution of specific NAcSh circuit components is unknown. METHODS: Bidirectional optogenetic manipulations were targeted to the principal NAcSh projection neurons and afferent pathways in mice during free feeding assays. Number of licks per bout of consumption was used as a measure of food palatability as it was confirmed to track sucrose concentration and subjective flavor preferences. RESULTS: Photoinhibition of NAcSh neurons, whether general or cell-type specific, was found to alter consumption without affecting its hedonic impact. Among the principal excitatory afferent pathways, we showed that ventral hippocampal (vHipp) input alone enhances palatability upon low-frequency photostimulation time-locked to consumption. This enhancement in palatability was independent of opioid signaling and not recapitulated by NAcSh or dopamine neuron photostimulation. We further demonstrated that vHipp input photostimulation is sufficient to condition a flavor preference, while its inhibition impedes sucrose-driven flavor preference conditioning. CONCLUSIONS: These results demonstrate a novel contribution of vHipp-NAcSh pathway activity to palatability that may relate to its innervation of a particular region or neuronal ensemble in the NAcSh. These findings are consistent with the evidence that vHipp-NAcSh activity is relevant to the pathophysiology of anhedonia and depression as well as the increasing appreciation of hippocampal involvement in people's food pleasantness ratings, hunger, and weight.

Optogenetic Activation of the Infralimbic Cortex Suppresses the Return of Appetitive Pavlovian-Conditioned Responding Following Extinction.

The infralimbic medial prefrontal cortex (IL) is important for suppressing learned behavior after extinction, but whether this function extends to responses acquired through appetitive Pavlovian conditioning is unclear. We trained male, Long-Evans rats to associate a white-noise conditional stimulus (CS; 10 s; 14 presentations per session) with 10% liquid sucrose (0.2 mL per CS presentation), and recorded entries into the fluid port during the CS. The CS was presented without sucrose in subsequent extinction and test sessions. Increasing IL activity with pretest microinfusions of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA; 0, 0.3 nmol; 0.3 µl/side) reduced the reinstatement of CS-elicited port entries. The same result was obtained when IL neurons that expressed Channelrhodopsin-2 (ChR2) were optically stimulated during CS presentations at test (473 nm, 5 ms pulses at 20 Hz for 10.2 s, unilateral). Optical stimulation of ChR2-expressing IL neurons during CS presentations also reduced spontaneous recovery and context-induced renewal. Furthermore, optical stimulation (1) during intertrial intervals had no impact on renewal, (2) depolarized ChR2-expressing IL pyramidal neurons in vitro, and (3) preferentially increased Fos in ChR2-expressing neurons. These novel converging data highlight a critical role for the IL in suppressing the return of appetitive Pavlovian-conditioned responding following extinction.

Varenicline Reduces Context-Induced Relapse to Alcohol-Seeking through Actions in the Nucleus Accumbens.

Varenicline, a pharmacotherapy for tobacco addiction, reduces alcohol consumption in humans and rodents. The therapeutic potential of varenicline would escalate if it also diminished conditioned responses elicited by alcohol-predictive cues, which can precipitate relapse in abstinent individuals. We investigated this application, along with the underlying neural substrates, using a robust preclinical assay in which relapse to alcohol-seeking was triggered by re-exposure to an alcohol-associated environmental context. Male, Long-Evans rats received Pavlovian conditioning sessions in which one auditory conditioned stimulus (CS+) was paired with 15% ethanol and a second conditioned stimulus (CS-) was not. Ethanol was delivered into a port for oral consumption and port entries triggered by each CS were recorded. Extinction was then conducted in a different context where the CS+ and CS- were presented without ethanol. To stimulate relapse, both cues were subsequently presented without ethanol in the prior conditioning context. Systemic varenicline (0, 0.5 or 2.5 mg/kg; intraperitoneal) blocked context-induced relapse to alcohol-seeking without affecting the ability to make a port entry. It also reduced context-induced relapse to sucrose-seeking, but only at the 2.5 mg/kg dose. Neuropharmacological studies showed that context-induced relapse to alcohol-seeking was attenuated by bilateral microinfusion of varenicline (0.3 µl/side) into the nucleus accumbens (NAc; 0 or 3.5 µg), but not the ventral tegmental area (0, 2 or 4 µg). These data show for the first time that varenicline reduces relapse triggered by contexts that predict alcohol, and suggest that nicotinic acetylcholine receptors in the NAc are critical for this effect.

A procedure to observe context-induced renewal of pavlovian-conditioned alcohol-seeking behavior in rats.

Environmental contexts in which drugs of abuse are consumed can trigger craving, a subjective Pavlovian-conditioned response that can facilitate drug-seeking behavior and prompt relapse in abstinent drug users. We have developed a procedure to study the behavioral and neural processes that mediate the impact of context on alcohol-seeking behavior in rats. Following acclimation to the taste and pharmacological effects of 15% ethanol in the home cage, male Long-Evans rats receive Pavlovian discrimination training (PDT) in conditioning chambers. In each daily (Mon-Fri) PDT session, 16 trials each of two different 10 sec auditory conditioned stimuli occur. During one stimulus, the CS+, 0.2 ml of 15% ethanol is delivered into a fluid port for oral consumption. The second stimulus, the CS-, is not paired with ethanol. Across sessions, entries into the fluid port during the CS+ increase, whereas entries during the CS- stabilize at a lower level, indicating that a predictive association between the CS+ and ethanol is acquired. During PDT each chamber is equipped with a specific configuration of visual, olfactory and tactile contextual stimuli. Following PDT, extinction training is conducted in the same chamber that is now equipped with a different configuration of contextual stimuli. The CS+ and CS- are presented as before, but ethanol is withheld, which causes a gradual decline in port entries during the CS+. At test, rats are placed back into the PDT context and presented with the CS+ and CS- as before, but without ethanol. This manipulation triggers a robust and selective increase in the number of port entries made during the alcohol predictive CS+, with no change in responding during the CS-. This effect, referred to as context-induced renewal, illustrates the powerful capacity of contexts associated with alcohol consumption to stimulate alcohol-seeking behavior in response to Pavlovian alcohol cues.