Optogenetic stimulation of infralimbic cortex projections to the paraventricular thalamus attenuates context-induced renewal.

Contexts associated with prior reinforcement can renew extinguished conditioned responding. The prelimbic (PL) and infralimbic (IL) cortices are thought to mediate the expression and suppression of conditioned responding, respectively. Evidence suggests that PL inputs to the paraventricular nucleus of the thalamus (PVT) drive the expression of cue-induced reinstatement of drug seeking and that IL inputs to the PVT mediate fear extinction retrieval. However, the role of these projections in renewal of appetitive Pavlovian conditioned responding is unknown. We trained male and female Long-Evans rats to associate a conditioned stimulus (CS; 10 s white noise) with delivery of a 10% sucrose unconditioned stimulus (US; .2 ml/CS) to a fluid port in a distinct context (Context A). We then extinguished responding by presenting the CS without the US in a different context (Context B). At test, rats were returned to Context A, and optogenetic stimulation was delivered to either the IL-to-PVT or PL-to-PVT pathway during CS presentations. Optically stimulating the IL-to-PVT, but not the PL-to-PVT pathway, attenuated ABA renewal of CS port entries, and this effect was similar in males and females. Further, rats self-administered optical stimulation of the IL-to-PVT but not the PL-to-PVT pathway suggesting that activation of the IL-to-PVT pathway is reinforcing. The effectiveness of optical stimulation parameters to activate neurons in the IL, PL and PVT was confirmed using Fos immunohistochemistry. These findings provide evidence for novel neural mechanisms in renewal of responding to a sucrose-predictive CS, as well as more generally in contextual processing and appetitive associative learning.

Brown A ，Chaudhri N 《-》

Corticostriatal Suppression of Appetitive Pavlovian Conditioned Responding.

The capacity to suppress learned responses is essential for animals to adapt in dynamic environments. Extinction is a process by which animals learn to suppress conditioned responding when an expected outcome is omitted. The infralimbic (IL) cortex to nucleus accumbens shell (NAcS) neural circuit is implicated in suppressing conditioned responding after extinction, especially in the context of operant cocaine-seeking behavior. However, the role of the IL-to-NAcS neural circuit in the extinction of responding to appetitive Pavlovian cues is unknown, and the psychological mechanisms involved in response suppression following extinction are unclear. We trained male Long Evans rats to associate a 10 s auditory conditioned stimulus (CS; 14 trials per session) with a sucrose unconditioned stimulus (US; 0.2 ml per CS) in a specific context, and then following extinction in a different context, precipitated a renewal of CS responding by presenting the CS alone in the original Pavlovian conditioning context. Unilateral, optogenetic stimulation of the IL-to-NAcS circuit selectively during CS trials suppressed renewal. In a separate experiment, IL-to-NAcS stimulation suppressed CS responding regardless of prior extinction and impaired extinction retrieval. Finally, IL-to-NAcS stimulation during the CS did not suppress the acquisition of Pavlovian conditioning but was required for the subsequent expression of CS responding. These results are consistent with multiple studies showing that the IL-to-NAcS neural circuit is involved in the suppression of operant cocaine-seeking, extending these findings to appetitive Pavlovian cues. The suppression of appetitive Pavlovian responding following IL-to-NAcS circuit stimulation, however, does not appear to be an extinction-dependent process.SIGNIFICANCE STATEMENT Extinction is a form of inhibitory learning through which animals learn to suppress conditioned responding in the face of nonreinforcement. We investigated the role of the IL cortex inputs to the NAcS in the extinction of responding to appetitive Pavlovian cues and the psychological mechanisms involved in response suppression following extinction. Using in vivo optogenetics, we found that stimulating the IL-to-NAcS neural circuit suppressed context-induced renewal of conditioned responding after extinction. In a separate experiment, stimulating the IL-to-NAcS circuit suppressed conditioned responding in an extinction-independent manner. These findings can be used by future research aimed at understanding how corticostriatal circuits contribute to behavioral flexibility and mental disorders that involve the suppression of learned behaviors.

Villaruel FR ，Martins M ，Chaudhri N 《-》

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

Villaruel FR ，Lacroix F ，Sanio C ，Sparks DW ，Chapman CA ，Chaudhri N ... -  《-》

Distinct recruitment of the hippocampal, thalamic, and amygdalar neurons projecting to the prelimbic cortex in male and female rats during context-mediated renewal of responding to food cues.

Persistent responding to food cues may underlie the difficulty to resist palatable foods and to maintain healthy eating habits. Renewal of responding after extinction is a model of persistent food seeking that can be used to study the underlying neural mechanisms. In context-mediated renewal, a return to the context in which the initial cue-food learning occurred induces robust responding to the cues that were extinguished elsewhere. Previous work found sex differences in context-mediated renewal and in the recruitment of the ventromedial prefrontal cortex (vmPFC) during that behavior. Males exhibited renewal of responding to food cues and had higher Fos induction in the prelimbic area (PL) of the vmPFC, while females failed to exhibit renewal of responding and had lower Fos induction in the PL. The main aim of the current study was to determine key components of the PL circuitry mediating renewal. The focus was on inputs from three areas important in appetitive associative learning and contextual processing: the amygdala, ventral hippocampal formation, and the paraventricular nucleus of the thalamus. The goal was to determine whether neurons from these areas that send direct projections to the PL (identified with a retrograde tracer) are selectively activated (Fos induction) during renewal and whether they are differently recruited in males and females. The Fos induction patterns demonstrated that the PL-projecting neurons in each of these areas were recruited in a sex-specific way that corresponded to the behavioral differences between males and females. These pathways were selectively activated in the male experimental group-the only group that showed renewal behavior. The findings suggest the pathways from the ventral hippocampal formation, paraventricular nucleus of the thalamus, and basolateral amygdala to the PL mediate renewal in males. The lack of recruitment in females suggests that under activation of these pathways may underlie their lack of renewal.

Anderson LC ，Petrovich GD 《-》

Neural correlates of recall and extinction in a rat model of appetitive Pavlovian conditioning.

Extinction is a fundamental form of inhibitory learning that is important for adapting to changing environmental contingencies. While numerous studies have investigated the neural correlates of extinction using Pavlovian fear conditioning and appetitive operant reward-seeking procedures, less is known about the neural circuitry mediating the extinction of appetitive Pavlovian responding. Here, we aimed to generate an extensive brain activation map of extinction learning in a rat model of appetitive Pavlovian conditioning. Male Long-Evans rats were trained to associate a conditioned stimulus (CS; 20 s white noise) with the delivery of a 10% sucrose unconditioned stimulus (US; 0.3 ml/CS) to a fluid port. Control groups also received CS presentations, but sucrose was delivered either during the inter-trial interval or in the home-cage. After conditioning, 1 or 6 extinction sessions were conducted in which the CS was presented but sucrose was withheld. We performed Fos immunohistochemistry and network connectivity analyses on a set of cortical, striatal, thalamic, and amygdalar brain regions. Neural activity in the prelimbic cortex, ventral orbitofrontal cortex, nucleus accumbens core, and paraventricular nucleus of the thalamus was greater during recall relative to extinction. Conversely, prolonged extinction following 6 sessions induced increased neural activity in the infralimbic cortex, medial orbitofrontal cortex, and nucleus accumbens shell compared to home-cage controls. All these structures were similarly recruited during recall on the first extinction session. These findings provide novel evidence for the contribution of brain areas and neural networks that are differentially involved in the recall versus extinction of appetitive Pavlovian conditioned responding.

Brown A ，Villaruel FR ，Chaudhri N 《-》