Prefrontal projections to the bed nuclei of the stria terminalis modulate the specificity of aversive memories.

Generalizing aversive memories helps organisms avoid danger, whereas discriminating between dissimilar situations promotes opportunistic behaviors. We identified a novel pathway that controls the contextual specificity of memory consolidation of inhibitory avoidance learning. Optogenetic inhibition of the rostral medial prefrontal cortex (mPFC)-to-anteroventral bed nuclei of the stria terminalis (avBST) pathway after a single footshock exacerbated stress hormonal output, and 2 d later promoted generalization to a novel context.

The Role of Acid-Sensing Ion Channel 1A (ASIC1A) in the Behavioral and Synaptic Effects of Oxycodone and Other Opioids.

Opioid-seeking behaviors depend on glutamatergic plasticity in the nucleus accumbens core (NAcc). Here we investigated whether the behavioral and synaptic effects of opioids are influenced by acid-sensing ion channel 1A (ASIC1A). We tested the effects of ASIC1A on responses to several opioids and found that mice had elevated behavioral responses to acute opioid administration as well as opioid seeking behavior in conditioned place preference (CPP).

Basolateral amygdala inputs to the nucleus accumbens shell modulate the consolidation of cued-response and inhibitory avoidance learning.

The basolateral amygdala (BLA) modulates different types of memory consolidation via distinct projections to downstream brain regions in multiple memory systems. Prior studies indicate that the BLA projects to the nucleus accumbens shell (NAshell) and that these regions interact to influence some types of behavior. Moreover, previous pharmacological work suggests the BLA and NAshell interact to influence memory.

Insular cortex subregions have distinct roles in cued heroin seeking after extinction learning and prolonged withdrawal in rats.

Evidence indicates that the anterior (aIC), but not posterior (pIC), insular cortex promotes cued reinstatement of cocaine seeking after extinction in rats. It is unknown whether these subregions also regulate heroin seeking and whether such involvement depends on prior extinction learning. To address these questions, we used baclofen and muscimol (BM) to inactivate the aIC or pIC bilaterally during a seeking test after extinction or prolonged withdrawal from heroin.

Still a "hidden island"? The rodent insular cortex in drug seeking, reward, and risk.

The insular cortex (IC) is implicated in risky decision making and drug-seeking behaviors, in a manner dissociable from natural reward seeking. However, evidence from rodent studies of motivated behaviors suggests that the role of the IC is not always consistent across procedures. Moreover, there is evidence of dissociation of function between posterior (pIC) and anterior (aIC) subregions in these behaviors.

Theoretical Considerations for Optimizing the Use of Optogenetics with Complex Behavior.

Optogenetic approaches have allowed researchers to address complex questions about behavior that were previously unanswerable. However, as optogenetic procedures involve a large parameter space across multiple dimensions, it is crucial to consider such parameters in conjunction with the behaviors under study. Here, we discuss strategies to optimize optogenetic approaches with complex behavior by identifying critical experimental design considerations, including frequency specificity, temporal precision, activity-controlled optogenetics, stimulation pattern, and cell-type specificity.

Effects of acid-sensing ion channel-1A (ASIC1A) on cocaine-induced synaptic adaptations.

Chronic drug abuse is thought to induce synaptic changes in nucleus accumbens medium spiny neurons (MSNs) that promote subsequent craving and drug-seeking behavior. Accumulating data suggest acid-sensing ion channels (ASICs) may play a critical role. In drug naïve mice, disrupting the ASIC1A subunit produced a variety of synaptic changes reminiscent of wild-type mice following cocaine withdrawal, including increased AMPAR/NMDAR ratio, increased AMPAR rectification, and increased dendrite spine density.

Infralimbic Projections to the Nucleus Accumbens Shell and Amygdala Regulate the Encoding of Cocaine Extinction Learning.

Prior evidence indicates that the infralimbic cortex (IL) mediates the ongoing inhibition of cocaine seeking following self-administration and extinction training in rats, specifically through projections to the nucleus accumbens shell (NAshell). Our own data indicate that IL activity immediately following an unreinforced lever press is critical for encoding the extinction contingencies in such procedures. Whether extinction encoding requires activity in the IL exclusively or also activity in its outputs, such as those to the NAshell and amygdala, is unknown.

Pair housing does not alter incubation of craving, extinction, and reinstatement after heroin self-administration in female and male rats.

Evidence suggests that single housing in rats acts as a chronic stressor, raising the possibilities that it contributes to measures of heroin craving and that pair housing ameliorates such measures. This study aimed to determine whether pair housing after heroin self-administration reduces the incubation of craving, extinction, and reinstatement of heroin seeking. Single-housed female and male Sprague-Dawley rats underwent daily 6-hr heroin self-administration, wherein active lever presses produced a heroin infusion paired with light/tone cues.

Carbonic anhydrase 4 disruption decreases synaptic and behavioral adaptations induced by cocaine withdrawal.

Cocaine use followed by withdrawal induces synaptic changes in nucleus accumbens (NAc), which are thought to underlie subsequent drug-seeking behaviors and relapse. Previous studies suggest that cocaine-induced synaptic changes depend on acid-sensing ion channels (ASICs). Here, we investigated potential involvement of carbonic anhydrase 4 (CA4), an extracellular pH-buffering enzyme.

Daily Optogenetic Stimulation of the Left Infralimbic Cortex Reverses Extinction Impairments in Male Rats Exposed to Single Prolonged Stress.

Post-traumatic stress disorder (PTSD) is associated with decreased activity in the prefrontal cortex. PTSD-like pathophysiology and behaviors have been observed in rodents exposed to a single prolonged stress (SPS) procedure. When animals are left alone for 7 days after SPS treatment, they show increased anxiety-like behavior and impaired extinction of conditioned fear, and reduced activity in the prefrontal cortex.

Environmental certainty influences the neural systems regulating responses to threat and stress.

Flexible calibration of threat responding in accordance with the environment is an adaptive process that allows an animal to avoid harm while also maintaining engagement of other goal-directed actions. This calibration process, referred to as threat response regulation, requires an animal to calculate the probability that a given encounter will result in a threat so they can respond accordingly. Here we review the neural correlates of two highly studied forms of threat response suppression: extinction and safety conditioning.

Theta oscillations in rat infralimbic cortex are associated with the inhibition of cocaine seeking during extinction.

Infralimbic cortical (IL) manipulations indicate that this region mediates extinction learning and suppresses cocaine seeking following cocaine self-administration. However, little work has recorded IL activity during the inhibition of cocaine seeking due to the difficulty of determining precisely when cocaine-seeking behaviour is inhibited within a cocaine-seeking session. The present study used in vivo electrophysiology to examine IL activity across extinction as well as during cocaine self-administration and reinstatement.

Infralimbic cortex functioning across motivated behaviors: Can the differences be reconciled?

The rodent infralimbic cortex (IL) is implicated in higher order executive functions such as reward seeking and flexible decision making. However, the precise nature of its role in these processes is unclear. Early evidence indicated that the IL promotes the extinction and ongoing inhibition of fear conditioning and cocaine seeking.

Amygdala-hippocampal interactions in synaptic plasticity and memory formation.

Memories of emotionally arousing events tend to endure longer than other memories. This review compiles findings from several decades of research investigating the role of the amygdala in modulating memories of emotional experiences. Episodic memory is a kind of declarative memory that depends upon the hippocampus, and studies suggest that the basolateral complex of the amygdala (BLA) modulates episodic memory consolidation through interactions with the hippocampus.

The medial entorhinal cortex mediates basolateral amygdala effects on spatial memory and downstream activity-regulated cytoskeletal-associated protein expression.

The basolateral amygdala (BLA) modulates the consolidation of dorsal hippocampus (DH)-dependent spatial and dorsolateral striatum (DLS)-dependent cued-response memories, often in competition with one another. Evidence suggests that a critical mechanism for BLA influences on memory consolidation is via effects on activity-regulated cytoskeletal-associated protein (ARC) in downstream brain regions. However, the circuitry by which the BLA modulates ARC in multiple competing memory systems remains unclear.

Bed nuclei of the stria terminalis modulate memory consolidation via glucocorticoid-dependent and -independent circuits.

There is extensive evidence that glucocorticoid hormones enhance memory consolidation, helping to ensure that emotionally significant events are well remembered. Prior findings suggest that the anteroventral region of bed nuclei of the stria terminalis (avBST) regulates glucocorticoid release, suggesting the potential for avBST activity to influence memory consolidation following an emotionally arousing learning event. To investigate this issue, male Sprague-Dawley rats underwent inhibitory avoidance training and repeated measurement of stress hormones, immediately followed by optogenetic manipulations of either the avBST or its projections to downstream regions, and 48 h later were tested for retention.

Postmeal Optogenetic Inhibition of Dorsal or Ventral Hippocampal Pyramidal Neurons Increases Future Intake.

Memory of a recently eaten meal can serve as a powerful mechanism for controlling future eating behavior because it provides a record of intake that likely outlasts most physiological signals generated by the meal. In support, impairing the encoding of a meal in humans increases the amount ingested at the next eating episode. However, the brain regions that mediate the inhibitory effects of memory on future intake are unknown.

Prefrontal-Bed Nucleus Circuit Modulation of a Passive Coping Response Set.

One of the challenges facing neuroscience entails localization of circuits and mechanisms accounting for how multiple features of stress responses are organized to promote survival during adverse experiences. The rodent medial prefrontal cortex (mPFC) is generally regarded as a key site for cognitive and affective information processing, and the anteroventral bed nuclei of the stria terminalis (avBST) integrates homeostatic information from a variety of sources, including the mPFC. Thus, we proposed that the mPFC is capable of generating multiple features (endocrine, behavioral) of adaptive responses via its influence over the avBST.

Overexpression of ASIC1A in the nucleus accumbens of rats potentiates cocaine-seeking behavior.

Acid-sensing ion channels (ASICs) are abundantly expressed in the nucleus accumbens core (NAcore), a region of the mesolimbocortical system that has an established role in regulating drug-seeking behavior. Previous work shows that a single dose of cocaine reduced the AMPA-to-NMDA ratio in Asic1a mice, an effect observed after withdrawal in wild-type mice, whereas ASIC1A overexpression in the NAcore of rats decreases cocaine self-administration. However, whether ASIC1A overexpression in the NAcore alters measures of drug-seeking behavior after the self-administration period is unknown.

A novel role for acid-sensing ion channels in Pavlovian reward conditioning.

Pavlovian fear conditioning has been shown to depend on acid-sensing ion channel-1A (ASIC1A); however, it is unknown whether conditioning to rewarding stimuli also depends on ASIC1A. Here, we tested the hypothesis that ASIC1A contributes to Pavlovian conditioning to a non-drug reward. We found effects of ASIC1A disruption depended on the relationship between the conditional stimulus (CS) and the unconditional stimulus (US), which was varied between five experiments.

Attenuation of cocaine seeking in rats via enhancement of infralimbic cortical activity using stable step-function opsins.

Rationale: The infralimbic cortex (IL) and its downstream projection target the nucleus accumbens shell (NAshell) mediate the active suppression of cocaine-seeking behavior. Although an optogenetic approach would be beneficial for stimulating the IL and its efferents to study their role during reinstatement of cocaine seeking, the use of channelrhodopsin introduces significant difficulties, as optimal stimulation parameters are not known.

Objectives: The present experiments utilized a stable step-function opsin (SSFO) to potentiate endogenous activity in the IL and in IL terminals in the NAshell during cocaine-seeking tests to determine how these manipulations affect cocaine-seeking behaviors.

Basolateral Amygdala Inputs to the Medial Entorhinal Cortex Selectively Modulate the Consolidation of Spatial and Contextual Learning.

Although evidence suggests that the basolateral amygdala (BLA) and dorsal hippocampus (DH) work together to influence the consolidation of spatial/contextual learning, the circuit mechanism by which the BLA selectively modulates spatial/contextual memory consolidation is not clear. The medial entorhinal cortex (mEC) is a critical region in the hippocampus-based system for processing spatial information. As an efferent target of the BLA, the mEC is a candidate by which the BLA influences the consolidation of such learning.

Neural systems mediating the inhibition of cocaine-seeking behaviors.

Over the past decades, research has targeted the neurobiology regulating cocaine-seeking behaviors, largely in the hopes of identifying potential targets for the treatment of cocaine addiction. Although much of this work has focused on those systems driving cocaine seeking, recently, studies examining the inhibition of cocaine-related behaviors have made significant progress in uncovering the neural systems that attenuate cocaine seeking. Such systems include the infralimbic cortex, nucleus accumbens shell, and hypothalamus.