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• Increased c-Fos expression in the lateral habenula after unpaired training. • More c-Fos–positive signals in the LHb-projecting dopaminergic midbrain of unpaired rats compared with paired rats. • LHb-lesioned animals exhibit normal performances in the paired and unpaired training. Neurons in the lateral habenula (LHb) are activated by reward omission and inhibited by reward delivery-reward processing functions opposite those of midbrain dopaminergic neurons. To further explore this, we examined the role of the LHb in associating a conditioned stimulus (CS) with the absence of an unconditioned stimulus (US) in an appetitive Pavlovian-conditioning paradigm. Rats underwent training in which a CS (light) was either paired (100% CS–US contingency) or unpaired (0% CS–US contiguity and negative contingency) with an US (food). Rats in the paired group exhibited steady acquisition of conditioned food-cup behaviors, while rats in the unpaired group showed low levels of response throughout training. After training, c-Fos levels were measured in the LHb, substantia nigra pars compacta (SNc), and ventral tegmental area (VTA) of rats in all groups. c-Fos levels were higher in the SNc/VTA of the paired group and the LHb of the unpaired group compared with the group with graded excitatory conditioning due to 50% of the CSs paired with USs and a low rate of USs presented during the intertrial interval and control groups for non-associative factors. The number of c-Fos–positive signals in LHb neurons projecting to dopaminergic midbrain neurons was higher in the unpaired group than in the paired group. Excitotoxic LHb lesions did not affect the acquisition of conditioned behaviors in the association of a CS with the presence or absence of an US. Significant increases in the numbers of c-Fos–positive neurons in the unpaired group suggest that LHb neurons engage in the process that associates a CS with the absence of an US. [ABSTRACT FROM AUTHOR]

Following a Pavlovian pairing procedure, alcohol-paired cues come to elicit behavioral responses that lead to alcohol consumption. Here we used an optogenetic approach to activate basolateral amygdala (BLA) axonal terminals targeting the shell of nucleus accumbens (AcbSh) and investigated a possible influence over cue-conditioned alcohol seeking and alcohol drinking, based on the demonstrated roles of these areas in behavioral responding to Pavlovian cues and in feeding behavior. Rats were trained to anticipate alcohol or sucrose following the onset of a discrete conditioned stimulus (CS). Channelrhodopsin-mediated activation of the BLA-to-AcbSh pathway concurrent with each CS disrupted cued alcohol seeking. Activation of the same pathway caused rapid cessation of alcohol drinking from a sipper tube. Neither effect was accompanied by an overall change in locomotion. Finally, the suppressive effect of photoactivation on cued-triggered seeking was also evidenced in animals trained with sucrose. Together these findings suggest that photoactivation of BLA terminals in the AcbSh can override the conditioned motivational properties of reward-predictive cues as well as unconditioned consummatory responses necessary for alcohol drinking. The findings provide evidence for a limbic-striatal influence over motivated behavior for orally consumed rewards, including alcohol. [ABSTRACT FROM AUTHOR]

Highlights: [•] Western diet (WD) impairs hippocampal-dependent cognitive function in rats. [•] WD is linked to blood–brain barrier (BBB) and glucoregulatory dysfunction. [•] Effects of WD on hippocampal cognitive and BBB function depend on obesity phenotype. [•] Diet-induced ketosis may have protective effects on the hippocampus and BBB. [•] Hippocampal-dependent cognitive dysfunction may precede and promote weight gain. [ABSTRACT FROM AUTHOR]

Abstract: The understanding of individual differences in responses to disgusting stimuli is important to gain more insight into the development of certain psychiatric disorders. The aim of this study was to investigate conditioned disgust responses, its potential overlap with conditioned fear responses (CRs) and the influence of disgust sensitivity on blood oxygen level–dependent responses. Yet even though current studies report evidence that disgust sensitivity is a vulnerability factor, the knowledge about the underlying neural mechanisms remains very limited. Two groups were exposed either to a disgust- or a fear-conditioning paradigm. Using functional magnetic resonance imaging, we identified a conjoint activated network including the cingulate cortex, the nucleus accumbens, the orbitofrontal cortex, and the occipital cortex within the disgust- and the fear-conditioning group. Moreover, we report evidence of increased insula activation in the disgust-conditioning group. In addition, functional connectivity analysis revealed increased interconnections, most pronounced within the insula in the high disgust sensitivity group compared with the low disgust sensitivity group. The conjunction results suggest that the conditioned responses in disgust and fear conditioning recruit the same neural network, implicating that different conditioned responses of aversive learning depend on a common neural network. Increased insula activation within the disgust-conditioning group might be attributable to heightened interoceptive processes, which might be more pronounced in disgust. Finally, the findings regarding disgust sensitivity are discussed with respect to vulnerability factors for certain psychiatric disorders. [Copyright &y& Elsevier]

The bed nucleus of the stria terminalis (BNST) is believed to be a critical relay between the central nucleus of the amygdala (CE) and the paraventricular nucleus of the hypothalamus in the control of hypothalamic–pituitary–adrenal (HPA) responses elicited by conditioned fear stimuli. If correct, lesions of CE or BNST should block expression of HPA responses elicited by either a specific conditioned fear cue or a conditioned context. To test this, rats were subjected to cued (tone) or contextual classical fear conditioning. Two days later, electrolytic or sham lesions were placed in CE or BNST. After 5 days, the rats were tested for both behavioral (freezing) and neuroendocrine (corticosterone) responses to tone or contextual cues. CE lesions attenuated conditioned freezing and corticosterone responses to both tone and context. In contrast, BNST lesions attenuated these responses to contextual but not tone stimuli. These results suggest CE is indeed an essential output of the amygdala for the expression of conditioned fear responses, including HPA responses, regardless of the nature of the conditioned stimulus. However, because lesions of BNST only affected behavioral and endocrine responses to contextual stimuli, the results do not support the notion that BNST is critical for HPA responses elicited by conditioned fear stimuli in general. Instead, the BNST may be essential specifically for contextual conditioned fear responses, including both behavioral and HPA responses, by virtue of its connections with the hippocampus, a structure essential to contextual conditioning. The results are also not consistent with the hypothesis that BNST is only involved in unconditioned aspects of fear and anxiety. [Copyright &y& Elsevier]

We have used cocaine-conditioned locomotion in rats as an animal model for cocaine-conditioned responses that contribute to drug craving and relapse in human addicts. The purpose of the present study was to examine the ability of the GABAB agonist, baclofen, to attenuate such associative responses. First, experiments were conducted to identify a dose range of baclofen that did not impede exploratory or spontaneous behavior. This dose range was used during testing for conditioned locomotion specific to a flashing light and metronome, which were previously associated with administration of cocaine (PAIRED group) or saline (UNPAIRED group). At 2.0 mg/kg, baclofen attenuated conditioned locomotion in PAIRED subjects to the level of UNPAIRED subjects receiving saline or 2.0 mg/kg baclofen. Considering the importance of glutamate transmission in the nucleus accumbens (NAc) during associative responses to reward-related stimuli, the effect of baclofen on extracellular levels of glutamate in the NAc was tested with microdialysis. Baclofen (2.0 mg/kg) did not alter basal glutamate levels. However, baclofen pretreatment prevented the predatory odor, 2,5-dihydro-2,4,5-trimethylthiazoline, from increasing glutamate levels. This is the first report of baclofen modulating extracellular levels of glutamate in the NAc. Baclofen may prove to have general utility for suppressing stimulus-evoked increases in NAc glutamate levels. This could explain its ability to prevent cocaine-conditioned responses. In summary, our results suggest that enhancing GABAB transmission inhibits cocaine-conditioned responses, possibly by suppressing glutamate transmission in the NAc. A better understanding of interactions between GABA and glutamate transmission in the NAc may lead to the development of pharmacotherapies for cocaine craving. [Copyright &y& Elsevier]