Behaviors central to the procurement and consumption of food are among those most fundamental to survival, but their inappropriate expression can lead to overeating and obesity. Nevertheless, we have ...a poor understanding of circuits that promote feeding independent of physiological demand. Here we demonstrate that activation of basal forebrain (BF) GABAergic neurons results in consumption of food as well as non-food items in well-fed mice, and performance of fictive eating in the absence of ingestible materials. In addition, stimulation of these cells disrupts defensive threat responses and elicits reward-like motivational effects. Finally, BF GABAergic activity triggers skilled predatory attacks of live prey and prey-like objects, but not social targets. These effects were entirely recapitulated by selective stimulation of BF GABAergic projections to the periaqueductal gray (PAG). Our results outline a potent circuit mechanism for increased feeding through recruitment of distinct but synergistic behaviors, and add to growing evidence that PAG is an important integrator of feeding-related activity.
Much is known about the neural circuits of conditioned fear and its relevance to understanding anxiety disorders, but less is known about other anxiety-related behaviors such as active avoidance. ...Using a tone-signaled, platform-mediated avoidance task, we observed that pharmacological inactivation of the prelimbic prefrontal cortex (PL) delayed avoidance. Surprisingly, optogenetic silencing of PL glutamatergic neurons did not delay avoidance. Consistent with this, inhibitory but not excitatory responses of rostral PL neurons were associated with avoidance training. To test the importance of these inhibitory responses, we optogenetically stimulated PL neurons to counteract the tone-elicited reduction in firing rate. Photoactivation of rostral (but not caudal) PL neurons at 4 Hz impaired avoidance. These findings suggest that inhibitory responses of rostral PL neurons signal the avoidability of a potential threat and underscore the importance of designing behavioral optogenetic studies based on neuronal firing responses.
Although both males and females become addicted to cocaine, females transition to addiction faster and experience greater difficulties remaining abstinent. We demonstrate an oestrous cycle-dependent ...mechanism controlling increased cocaine reward in females. During oestrus, ventral tegmental area (VTA) dopamine neuron activity is enhanced and drives post translational modifications at the dopamine transporter (DAT) to increase the ability of cocaine to inhibit its function, an effect mediated by estradiol. Female mice conditioned to associate cocaine with contextual cues during oestrus have enhanced mesolimbic responses to these cues in the absence of drug. Using chemogenetic approaches, we increase VTA activity to mechanistically link oestrous cycle-dependent enhancement of VTA firing to enhanced cocaine affinity at DAT and subsequent reward processing. These data have implications for sexual dimorphism in addiction vulnerability and define a mechanism by which cellular activity results in protein alterations that contribute to dysfunctional learning and reward processing.
Individuals use both passive and active defensive responses to environmental threats. Much is known about the neural circuits of passive defensive responses (e.g., freezing), but less is known about ...the substrates of active defensive responses (e.g., avoidance). We developed an active avoidance task in which rats learn to avoid a tone-signaled footshock by stepping onto a nearby platform. An advantage of this task is that freezing, which can interfere with avoidance, is reduced, thereby facilitating comparison of the effects of manipulations on avoidance versus freezing. After 10 d of avoidance training, rats were infused with muscimol to pharmacologically inactivate the prelimbic cortex (PL), infralimbic cortex (IL), ventral striatum (VS), or basolateral amygdala (BLA). Inactivating PL, VS, or BLA all impaired avoidance expression, but these areas differed with respect to freezing. Inactivating BLA decreased freezing consistent with loss of the tone-shock association, whereas inactivation of VS increased freezing consistent with loss of avoidance memory. Inactivation of PL had no effect on freezing. Inactivation of IL did not impair avoidance expression but did impair avoidance extinction. Our findings suggest that active avoidance is mediated by prefrontal-striatal circuits, which may be overactive in individuals suffering from trauma-related disorders.
Persistent avoidance is a prominent symptom of anxiety disorders and is often resistant to extinction-based therapies. Little is known about the circuitry mediating persistent avoidance. Using a ...recently described platform-mediated active avoidance task, we assessed activity in several structures with c-Fos immuno-labeling. In Task 1, rats were conditioned to avoid a tone-signaled shock by moving to a safe platform, and then were extinguished over two days. One day later, failure to retrieve extinction correlated with increased activity in the prelimbic prefrontal cortex (PL), ventral striatum (VS), and basal amygdala (BA), and decreased activity in infralimbic prefrontal cortex (IL), consistent with pharmacological inactivation studies. In Task 2, the platform was removed during extinction training and fear (suppression of bar pressing) was extinguished to criterion over 3-5 days. The platform was then returned in a post-extinction test. Under these conditions, avoidance levels were equivalent to Experiment 1 and correlated with increased activity in PL and VS, but there was no correlation with activity in IL or BA. Thus, persistent avoidance can occur independently of deficits in fear extinction and its associated structures.
Alcohol-use disorder (AUD) is the most prevalent substance-use disorder worldwide. There is substantial individual variability in alcohol drinking behaviors in the population, the neural circuit ...mechanisms of which remain elusive. Utilizing in vivo electrophysiological techniques, we find that low alcohol drinking (LAD) mice have dramatically higher ventral tegmental area (VTA) dopamine neuron firing and burst activity. Unexpectedly, VTA dopamine neuron activity in high alcohol drinking (HAD) mice does not differ from alcohol naive mice. Optogenetically enhancing VTA dopamine neuron burst activity in HAD mice decreases alcohol drinking behaviors. Circuit-specific recordings reveal that spontaneous activity of nucleus accumbens-projecting VTA (VTA-NAc) neurons is selectively higher in LAD mice. Specifically activating this projection is sufficient to reduce alcohol consumption in HAD mice. Furthermore, we uncover ionic and cellular mechanisms that suggest unique neuroadaptations between the alcohol drinking groups. Together, these data identify a neural circuit responsible for individual alcohol drinking behaviors.
Rationale
Recovery from a traumatic experience requires extinction of cue-based fear responses, a process that is impaired in post-traumatic stress disorder. While studies suggest a link between fear ...behavioral flexibility and noradrenaline signaling, the role of specific receptors and brain regions in these effects is unclear.
Objectives
Here, we examine the role of prazosin, an α1-adrenergic receptor (α1-AR) antagonist, in auditory fear conditioning and extinction.
Methods
C57Bl/6N mice were subjected to auditory fear conditioning and extinction in combination with systemic (0.1–2 mg/kg) or local microinjections (3 or 6 mM) of the α1-AR antagonist prazosin into the prelimbic division of medial prefrontal cortex or basolateral amygdala. Conditioned fear and anxiety-like behaviors were compared with vehicle-injected control animals.
Results
Mice that received systemic prazosin prior to fear conditioning exhibited similar initial levels of cue-elicited freezing compared to vehicle controls on the following day. However, at all doses tested, fear that was acquired during prazosin treatment was more readily extinguished, whereas anxiety-like behavior on the day of extinction was unaffected. A similar pattern of results was observed when prazosin was microinjected into the basolateral amygdala but not the prelimbic cortex. In contrast to pre-conditioning injections, prazosin administration prior to extinction had no effect on freezing.
Conclusions
Our results indicate that α1-AR activity during aversive conditioning is dispensable for memory acquisition but renders conditioned fear more impervious to extinction. This suggests that behavioral flexibility is constrained by noradrenaline at the time of initial learning via activation of a specific AR isoform.
The original version of this Article contained an error in the spelling of the author Scott Edwards, which was incorrectly given as Scott Edward. This has now been corrected in both the PDF and HTML ...versions of the Article.
Abstract
Introduction
Spatial learning in rodents is useful for addressing a variety of research questions. We set out to create a fully automated spatial learning task that required rodents to make ...a sequence of cued navigational decisions. We used this maze to investigate the impact of sleep on insight gain, a sudden rather than gradual acquisition of a skill or behavior.
Methods
We designed a circular four-quadrant elevated maze. Each quadrant had three choice points on a branched arm, consisting of a reward well and cue light. To discourage rats from backtracking, motorized doors were placed between quadrants. Rats were trained to follow the light for a water reward. Their position was tracked by custom MATLAB code processing live video from a ceiling-mounted camera; the code also controlled all components of the maze, calculated and presented novel routes through the maze, analyzed results in real time, and maintained records of each rat across sessions. After an average of five days rats reached criterion in pretraining (following lights in pseudorandom positions) and were taught a hidden rule: the direction cued on the second quadrant was the correct direction on the fourth (uncued) quadrant. Rats completed one session each in the morning and afternoon, separated by 3h of sleep opportunity or sleep disruption, achieved by gentle handling. This was repeated after a night of sleep opportunity or sleep disruption for a total of four sessions.
Results
Rats quickly learned and consistently chose the correct well, remaining motivated for 96 consecutive trials. Rats were said to have gained insight if they demonstrated significant learning of the hidden rule. Although no animals have yet met this criterion, there was a trend of sleep-disrupted rats performing worse, suggesting that sleep plays an important role in consolidating the spatial rules of the task.
Conclusion
The versatility of this maze can accommodate many tasks not limited to insight gain specifically. Delivering rewards consistently at multiple distinct locations is a valuable technique for investigating spatial learning, navigation, and decision making, making this maze a powerful tool for investigating interventions for disease models that implicate the hippocampus or striatum.
Support (if any)
Responding to environmental threats and securing nourishment are the most fundamental actions an animal needs to perform to ensure survival. In the past few decades, a lot of emphasis has been given ...to the basal forebrain (BF) cholinergic influence in threat-related cue processing and food intake, however very little is known about the functional role of other more abundant neural populations in the BF. Here, I sought to determine how BF GABAergic neurons contribute to defensive threat responses and feeding behaviors. First, I examined if BF GABAergic neurons are necessary for fear memory retrieval, then I assessed when this neuronal population is recruited. Using optogenetic tools, I discovered that BF GABAergic neurons support cue-evoked freezing and that activity of these neurons during fear conditioning is necessary to influence freezing at later timepoints. Furthermore, I demonstrated that activity of this neuronal population modulates cue-elicit freezing during early extinction training, but do not enhance extinction memory retrieval. While several studies demonstrate that BF GABAergic neurons send long-range projections to the medial prefrontal cortex (mPFC), a key structure for fear expression, how BF GABAergic inputs in mPFC might affect fear memory retrieval remains unexplored. In this study, I provided evidence that fear expression modulation is mediated through BF GABAergic afferents in mPFC. Lastly, I evaluated how the activation of BF GABAergic neurons influence feeding drive. I uncovered that photostimulation of BF GABAergic neurons results in consumption of food as well as non-edible items in well-fed mice. In addition, stimulation of these cells disrupts defensive threat responses and elicits reward-like motivational effects. Finally, BF GABAergic activity triggers skilled predatory attack of live prey and prey-like objects. Interestingly, these effects were entirely recapitulated by selective stimulation of BF GABAergic projections to the periaqueductal gray (PAG). Taken together, our findings demonstrate that BF GABAergic neurons are involved in regulating fear expression and inhibition, feeding drive and reward.
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