Borders and comparative cytoarchitecture of the perirhinal and postrhinal cortices in an F1 hybrid mouse.

We examined the cytoarchitectonic and chemoarchitectonic organization of the cortical regions associated with the posterior rhinal fissure in the mouse brain, within the framework of what is known about these regions in the rat. Primary observations were in a first-generation hybrid mouse line, B6129PF/J1. The F1 hybrid was chosen because of the many advantages afforded in the study of the molecular and cellular bases of learning and memory. Comparisons with the parent strains, the C57BL6/J and 129P3/J are also reported. Mouse brain tissue was processed for visualization of Nissl material, myelin, acetyl cholinesterase, parvalbumin, and heavy metals. Tissue stained for heavy metals by the Timm's method was particularly useful in the assignment of borders and in the comparative analyses because the patterns of staining were similar across species and strains. As in the rat, the areas examined were parcellated into 2 regions, the perirhinal and the postrhinal cortices. The perirhinal cortex was divided into areas 35 and 36, and the postrhinal cortex was divided into dorsal (PORd) and ventral (PORv) subregions. In addition to identifying the borders of the perirhinal cortex, we were able to identify a region in the mouse brain that shares signature features with the rat postrhinal cortex.

Normal Aging does Not Impair Orbitofrontal-Dependent Reinforcer Devaluation Effects.

Normal aging is associated with deficits in cognitive flexibility thought to depend on prefrontal regions such as the orbitofrontal cortex (OFC). Here, we used Pavlovian reinforcer devaluation to test whether normal aging might also affect the ability to use outcome expectancies to guide appropriate behavioral responding, which is also known to depend on the OFC. Both young and aged rats were trained to associate a 10-s conditioned stimulus (CS+) with delivery of a sucrose pellet. After training, half of the rats in each age group received the sucrose pellets paired with illness induced by LiCl injections; the remaining rats received sucrose and illness explicitly unpaired. Subsequently, responding to the CS+ was assessed in an extinction probe test. Although aged rats displayed lower responding levels overall, both young and aged rats conditioned to the CS+ and developed a conditioned taste aversion following reinforcer devaluation. Furthermore, during the extinction probe test, both young and aged rats spontaneously attenuated conditioned responding to the cue as a result of reinforcer devaluation. These data show that normal aging does not affect the ability to use expected outcome value to appropriately guide Pavlovian responding. This result indicates that deficits in cognitive flexibility are dissociable from other known functions of prefrontal - and particularly orbitofrontal - cortex.

The role of the nucleus accumbens in knowing when to respond.

While knowing what to expect is important, it is equally important to know when to expect it and to respond accordingly. This is apparent even in simple Pavlovian training situations in which animals learn to respond more strongly closer to reward delivery. Here we report that the nucleus accumbens core, an area well-positioned to represent information about the timing of impending rewards, plays a critical role in this timing function.

Nucleus Accumbens Core and Shell are Necessary for Reinforcer Devaluation Effects on Pavlovian Conditioned Responding.

The nucleus accumbens (NA) has been hypothesized to be part of a circuit in which cue-evoked information about expected outcomes is mobilized to guide behavior. Here we tested this hypothesis using a Pavlovian reinforcer devaluation task, previously applied to assess outcome-guided behavior after damage to regions such as the orbitofrontal cortex and amygdala that send projections to NA. Rats with sham lesions or neurotoxic lesions of either the core or shell subdivision of NA were trained to associate a 10-s CS+ with delivery of three food pellets. After training, half of the rats in each lesion group received food paired with illness induced by LiCl injections; the remaining rats received food and illness unpaired. Subsequently, responding to the CS+ was assessed in an extinction probe test. Both sham and lesioned rats conditioned to the CS+ and formed a conditioned taste aversion. However only sham rats reduced their conditioned responding as a result of reinforcer devaluation; devalued rats with lesions of either core or shell showed levels of responding that were similar to lesioned, non-devalued rats. This impairment was not due to the loss of motivational salience conferred to the CS+ in lesioned rats as both groups responded similarly for the cue in conditioned reinforcement testing. These data suggest that NA core and shell are part of a circuit necessary for the use of cue-evoked information about expected outcomes to guide behavior.

Ventral striatal neurons encode the value of the chosen action in rats deciding between differently delayed or sized rewards.

The ventral striatum (VS) is thought to serve as a gateway whereby associative information from the amygdala and prefrontal regions can influence motor output to guide behavior. If VS mediates this "limbic-motor" interface, then one might expect neural correlates in VS to reflect this information. Specifically, neural activity should reflect the integration of motivational value with subsequent behavior. To test this prediction, we recorded from single units in VS while rats performed a choice task in which different odor cues indicated that reward was available on the left or on the right. The value of reward associated with a left or rightward movement was manipulated in separate blocks of trials by either varying the delay preceding reward delivery or by changing reward size. Rats' behavior was influenced by the value of the expected reward and the response required to obtain it, and activity in the majority of cue-responsive VS neurons reflected the integration of these two variables. Unlike similar cue-evoked activity reported previously in dopamine neurons, these correlates were only observed if the directional response was subsequently executed. Furthermore, activity was correlated with the speed at which the rats' executed the response. These results are consistent with the notion that VS serves to integrate information about the value of an expected reward with motor output during decision making.

Neural correlates of inflexible behavior in the orbitofrontal-amygdalar circuit after cocaine exposure.

Addiction is characterized by compulsive or inflexible behavior, observed both in the context of drug-seeking and in contexts unrelated to drugs. One possible contributor to these inflexible behaviors may be drug-induced dysfunction within circuits that support behavioral flexibility, including the basolateral amygdala (ABL) and the orbitofrontal cortex (OFC). Here we describe data demonstrating that chronic cocaine exposure causes long-lasting changes in encoding properties in the ABL and the OFC during learning and reversal in an odor-guided task. In particular, these data suggest that inflexible encoding in ABL neurons may be the proximal cause of cocaine-induced behavioral inflexibility, and that a loss of outcome-expectant encoding in OFC neurons could be a more distal contributor to this impairment. A similar mechanism of drug-induced orbitofrontal-amygdalar dysfunction may cause inflexible behavior when animals and addicts are exposed to drug-associated cues and contexts.

Cocaine-induced decision-making deficits are mediated by miscoding in basolateral amygdala.

Addicts and drug-experienced animals have decision-making deficits in reversal-learning tasks and more complex 'gambling' variants. Here we show evidence that these deficits are mediated by persistent encoding of outdated associative information in the basolateral amygdala. Cue-selective neurons in the basolateral amygdala, recorded in cocaine-treated rats, failed to change cue preference during reversal learning. Further, the presence of these neurons was critical to the expression of the reversal-learning deficit in the cocaine-treated rats.

Withdrawal from cocaine self-administration produces long-lasting deficits in orbitofrontal-dependent reversal learning in rats.

Drug addicts make poor decisions. These decision-making deficits have been modeled in addicts and laboratory animals using reversal-learning tasks. However, persistent reversal-learning impairments have been shown in rats and monkeys only after noncontingent cocaine injections. Current thinking holds that to represent the human condition effectively, animal models of addiction must utilize self-administration procedures in which drug is earned contingently; thus, it remains unclear whether reversal-learning deficits caused by noncontingent cocaine exposure are relevant to addiction. To test whether reversal learning deficits are caused by contingent cocaine exposure, we trained rats to self-administer cocaine, assessed cue-induced cocaine seeking in extinction tests after 1 and 30 d of withdrawal, and then tested for reversal learning more than a month later. We found robust time-dependent increases in cue-induced cocaine seeking in the two extinction tests (incubation of craving) and severe reversal-learning impairments.

Basolateral amygdala lesions abolish orbitofrontal-dependent reversal impairments.

Damage to orbitofrontal cortex (OFC) has long been associated with deficits in reversal learning. OFC damage also causes inflexible associative encoding in basolateral amygdala (ABL) during reversal learning. Here we provide a critical test of the hypothesis that the reversal deficit in OFC-lesioned rats is caused by this inflexible encoding in ABL. Rats with bilateral neurotoxic lesions of OFC, ABL, or both areas were tested on a series of two-odor go/no-go discrimination problems, followed by two serial reversals of the final problem. As expected, all groups acquired the initial problems at the same rate, and rats with OFC lesions were slower to acquire the reversals than sham controls. This impairment was abolished by accompanying ABL lesions, while ABL lesions alone had no effect on reversal learning. These results are consistent with the hypothesis that OFC facilitates cognitive flexibility by promoting updating of associative encoding in downstream brain areas.