Recent work has shown the importance of perineuronal nets (PNNs) in modulating neuronal function and plasticity. Functional studies increasingly manipulate PNNs to probe their role in learning and memory, yet interpreting these manipulations requires knowing which cell types PNNs surround, information that remains incomplete for several brain regions. This study focuses on the prelimbic cortex to determine the percentage of specific interneurons and pyramidal cells that are surrounded by PNNs in male rats and mice. We used immunohistochemistry to assess prelimbic cortex cells containing parvalbumin (PV), glutamate decarboxylase (GAD65/67), and/or calcium kinase II (CamKII), and Wisteria floribunda agglutinin to identify PNNs. Cells with PV, GAD65/67 and/or CamKII were counted and the percentage with PNNs was calculated. Among the cell types examined, PV-expressing interneurons showed the highest frequency of PNN association in the prelimbic cortex of both rats and mice, followed by GAD65/67-expressing interneurons. No CamKII-positive cells had PNNs in rats or mice. PV-only and GAD-only cells were much more likely to have PNNs in mice than in rats. In both species, a small percentage of PNNs surround cells that had no detectable immunolabeling. These findings indicate that PV interneurons are most likely to have PNNs in layers 5/6 of the prelimbic cortex, but species differences suggest caution in designing and interpreting experiments that manipulate PNNs, particularly when generalizing between rat and mouse models.

OBJECTIVE:Glucagon-like peptide-1 receptor (GLP-1R) agonists reduce food intake and body weight, suggesting they should be avoided in anorexia nervosa. However, preclinical evidence that these drugs reduce activity and reward-seeking behavior raises the possibility that they might attenuate the compulsive-like hyperactivity central to ABA pathology and slow weight loss. Here, we employed a widely used rodent model of AN (activity-based anorexia, ABA) to determine whether a GLP-1R agonist would worsen or rather lessen weight loss and hyperactivity. METHOD:Female mice that had continuous access to a running wheel and time-restricted food availability received systemic administration of a GLP-1R agonist, a GLP-1R antagonist, or vehicle once daily before food presentation (N = 10/group). RESULTS:GLP-1R agonist treatment exacerbated ABA-associated weight loss, confirming the concern that appetite suppression would worsen outcomes and failing to support the possibility that reduced compulsive-like activity might provide benefit. This effect was driven by a further suppression of food intake, while wheel running remained unchanged. Pharmacological blockade of GLP-1R signaling had no detectable effect on any parameter monitored relative to vehicle controls. DISCUSSION:These findings provide the first experimental evidence that GLP-1R agonism worsens outcomes in an animal model of anorexia nervosa. The lack of effect of GLP-1R antagonism suggests endogenous GLP-1 signaling does not substantially contribute to ABA pathology. Together, these data raise caution regarding the use of GLP-1R agonists in individuals vulnerable to restrictive eating as they are unlikely to reduce the motivation for excessive activity and can further reduce food intake.

Cocaine and methamphetamine use disorders pose public health concerns due to the high propensity for relapse driven by persistent drug-associated memories. Output from the medial prefrontal cortex (mPFC) regulates relapse and is controlled by parvalbumin (PV) interneurons, which are surrounded by perineuronal nets (PNNs) that support precise PV neuron firing. We previously showed that removal of mPFC PNNs, which reduces PV firing, disrupted reconsolidation of a cocaine self-administration memory when rats were given a novel, but not familiar, memory retrieval session. Ketamine rapidly suppresses PV neuron output, so we tested whether a single low dose (6 mg/kg) administered before or after a familiar or novel memory retrieval session altered cocaine cue reinstatement. Ketamine given prior to the novel, but not familiar, retrieval session reduced cue reinstatement in male Sprague-Dawley rats. In addition, both ketamine treatments combined with a novel retrieval session reduced PNN intensity around PV neurons after cue reinstatement, suggesting that PNN decreases may be unrelated to reinstatement. However, ketamine reduced the number of c-Fos-activated PV neurons immediately after the novel memory retrieval session, indicating that ketamine may reduce reinstatement through reduced PV neuron function at the time of memory retrieval. Ketamine given just prior to a novel memory retrieval session also reduced cue-induced reinstatement in rats trained for methamphetamine, but not fentanyl or sucrose self-administration. Collectively, these studies show that a single, low dose of ketamine combined with a novel memory retrieval reduces psychostimulant-seeking behavior, and may help delineate the mechanisms for ketamine-reduced relapse in psychostimulant use disorders.

Anorexia nervosa is a severe psychiatric disorder characterized by persistent food restriction and often excessive physical activity, implicating dysfunction in neural circuits governing motivation, reward, and behavioral persistence. The nucleus accumbens (NAc) is a central component of these circuits, yet synaptic and cellular adaptations within this region during anorexia-like states remain poorly defined. Using the activity-based anorexia (ABA) paradigm in adult female mice, we examined glutamatergic transmission and intrinsic neuronal properties in the NAc shell. ABA exposure produced rapid weight loss, reduced food intake, and progressively increased running-wheel activity. Biochemical analyses of NAc shell tissue revealed elevated membrane-associated GluA2 AMPA receptor protein. Consistent with this finding, whole-cell patch-clamp recordings from medium spiny neurons showed increased amplitude of spontaneous excitatory postsynaptic currents. ABA also enhanced intrinsic neuronal excitability, reflected by greater firing in response to depolarizing current injections. Together, these convergent biochemical and electrophysiological results demonstrate that ABA induces coordinated postsynaptic strengthening and increased intrinsic excitability in NAc shell medium spiny neurons. These adaptations suggest a sustained increase in accumbal output that may bias motivational circuit function and contribute to excessive activity and suppressed feeding during anorexia-like conditions, paralleling glutamatergic plasticity observed in other compulsive disorders, including substance use disorder.

Opioid use disorder poses a complex challenge marked by high relapse rates, which stem from an intricate interplay between physical dependence and psychological vulnerabilities. Previous research has demonstrated that hyperbaric oxygen treatment (HBOT), exposure to 100% oxygen under elevated pressure, reduced physical withdrawal symptoms in morphine-dependent male mice. However, remaining unknown are the effects of HBOT in female mice, its impact on the rewarding and aversive behaviors associated with morphine exposure, and the underlying mechanisms that may be driving these effects. We confirmed the beneficial effects of HBOT in reducing physical withdrawal signs in male mice and, for the first time, demonstrated that HBOT also alleviates these symptoms in female mice. HBOT had no significant effect on morphine-conditioned place preference or conditioned place aversion, suggesting that our HBOT regimen does not influence motivated behaviors. Finally, we show that HBOT treatment reduces microglial soma volume in morphine-treated male and female mice in the paraventricular thalamus, suggesting a shift towards a "resting" state after HBOT. These findings collectively suggest that HBOT may offer a promising, non-pharmacological approach to mitigating opioid withdrawal symptoms across sexes, potentially through modulation of microglia.

Stress is a potent trigger for drug-seeking behaviors in both rodents and humans with a history of substance use. Kappa opioid receptors (kORs) play a critical role in mediating stress responses. Our previous studies in the ventral tegmental area (VTA) demonstrated that acute stress activates kORs to block long-term potentiation at GABAA synapses on dopamine neurons (LTPGABA) and triggers stress-induced reinstatement of cocaine seeking. Here we identify the specific GABAergic afferents affected by stress, the precise localization of kORs within the VTA, and show that VTA kOR activation is sufficient to drive reinstatement. In male and female mice, we optogenetically activated specific GABAergic afferents and found that nucleus accumbens (NAc)-to-VTA, but not lateral hypothalamus-to-VTA projections, exhibit stress-sensitive LTPGABA Using a conditional knock-out approach, we found that selectively deleting kORs from NAc neurons but not from dopamine cells prevents stress-induced block of LTPGABA Selectively activating dynorphin-containing NAc neurons with an excitatory DREADD mimics acute stress, preventing LTPGABA at VTA synapses. We furthermore demonstrated that without acute stress, microinjection of a selective kOR agonist directly into the VTA of male rats facilitates cocaine reinstatement without similarly affecting sucrose-motivated responding, demonstrating the critical role of kORs in stress-induced cocaine reinstatement. Our results show that kORs on GABAergic NAc nerve terminals in the VTA underlie loss of LTPGABA that may drive stress-induced addiction-related behaviors. Our work highlights the importance of inhibitory inputs for controlling dopamine neuron excitability in the context of addiction and contributes to defining the circuit involved in stress-induced drug reinstatement.

Abstract Anorexia nervosa (AN) remains one of the most lethal mental health disorders and is poorly understood from a neurobiological perspective. The most widely used animal model of AN is activity‐based anorexia (ABA) where scheduled food presentation leads to a spontaneous maladaptive increase in running‐wheel activity and rapid weight loss in rodents, recapitulating specific aspects of AN. Research using the ABA paradigm to probe the role of hedonic and homeostatic circuits has indicated that the hypothalamic proopiomelanocortin (POMC) system may play a role in both the increased activity and reduced food intake observed. Previous work has shown that Pomc mRNA and its peptide product beta‐endorphin (β‐end) are increased during the onset of ABA. β‐end is reinforcing and increases locomotor activity, and mice lacking the mu opioid receptor (MOR), the primary target of β‐end, display blunted food‐anticipatory activity in the ABA paradigm. Thus, the current work was designed to determine if aspects of ABA would be diminished in mice lacking β‐end. We did not find any significant differences in wheel‐running, food intake, or body weight loss in β‐end knockout mice of either sex during ABA compared to wild‐type littermates. Therefore, we conclude that the development of ABA does not require β‐end.

The medial prefrontal cortex (mPFC) is a major contributor to relapse to cocaine in humans and to reinstatement behavior in rodent models of cocaine use disorder. Output from the mPFC is modulated by parvalbumin (PV)-containing fast-spiking interneurons, the majority of which are surrounded by perineuronal nets (PNNs). Here we tested whether chondroitinase ABC (ABC)- mediated removal of PNNs prevented the acquisition or reconsolidation of a cocaine self-administration memory. ABC injections into the dorsal mPFC prior to training attenuated the acquisition of cocaine self-administration. Also, ABC given 3 days prior to but not 1 hr after memory reactivation blocked cue-induced reinstatement. However, reduced reinstatement was present only in rats given a novel reactivation contingency, suggesting that PNNs are required for the updating of a familiar memory. In naive rats, ABC injections into mPFC did not alter excitatory or inhibitory puncta on PV cells but reduced PV intensity. Whole-cell recordings revealed a greater inter-spike interval 1 hr after ABC, but not 3 days later. In vivo recordings from the mPFC and dorsal hippocampus (dHIP) during novel memory reactivation revealed that ABC in the mPFC prevented reward-associated increases in beta and gamma activity as well as phase-amplitude coupling between the dHIP and mPFC. Together, our findings show that PNN removal attenuates the acquisition of cocaine self-administration memories and disrupts reconsolidation of the original memory when combined with a novel reactivation session. Further, reduced dHIP/mPFC coupling after PNN removal may serve as a key biomarker for how to disrupt reconsolidation of cocaine memories and reduce relapse.

Parvalbumin (PV)-positive cells are GABAergic fast-spiking interneurons that modulate the activity of pyramidal neurons in the medial prefrontal cortex (mPFC) and their output to brain areas associated with learning and memory. The majority of PV cells within the mPFC are surrounded by a specialized extracellular matrix structure called the perineuronal net (PNN). We have shown that removal of PNNs with the enzyme chondroitinase-ABC (Ch-ABC) in the mPFC prevents the consolidation and reconsolidation of cocaine-associated conditioned place preference (CPP) memories. Here we examined the extent to which retrieval of a CPP memory during cocaine-primed reinstatement altered the levels and function of PV neurons and their surrounding PNNs during the reconsolidation period. We further determined the extent to which PNN removal prior to reinstatement altered PV intensity levels and PV cell function. Male Sprague-Dawley rats were trained for cocaine-induced conditioned place preference (CPP) followed by extinction training, microinjection of Ch-ABC in the prelimbic PFC, and cocaine-induced reinstatement. Rats were sacrificed immediately prior to reinstatement or at 2 h, 6 h, or 48 h after reinstatement for immunohistochemistry or 2 h later for electrophysiology. Our findings indicate that PNN removal only partially diminished reinstatement. Cocaine-primed reinstatement produced only minor changes in PNN or PV intensity in vehicle controls. However, after PNN removal, the intensity of remaining PNN-surrounded PV cells was decreased at all times except at 2 h post-reinstatement, at which time cocaine increased PV intensity. Consistent with this, in vehicle controls, PV neurons naturally devoid of PNNs showed a similar pattern to Ch-ABC-treated rats prior to and after cocaine reinstatement, suggesting a protective effect of PNNs on cocaine-induced changes in PV intensity. Using whole-cell patch-clamp, cocaine-primed reinstatement in Ch-ABC-treated rats decreased the number of elicited action potentials but increased excitatory synaptic transmission, which may have been compensatory. These findings suggest that without PNNs, cocaine-induced reinstatement produces rapid changes in PV intensity and PV cell excitability, which may in turn regulate output of the mPFC post-memory retrieval and diminish the maintenance of cocaine memory during reconsolidation.

Fatty acid composition across functional brain regions was determined in bovine brains collected from cattle that were provided supplements of calcium salts containing either palm or fish oil. The Angus cattle were divided into two groups, with one group offered the supplement of calcium salts of palm oil and the other offered the calcium salts of fish oil (n = 5 females and n = 5 males/supplement) for 220 days. These supplements to the basal forage diet were provided ad libitum as a suspension in dried molasses. The fish oil exclusively provided eicosapentaenoic acid (EPA, C20:5 n-3) and docosahexaenoic acid (DHA, C22:6 n-3). The functional regions were dissected from the entire brains following commercial harvest. While the cattle provided diets supplemented with the calcium salts of palm oil had increased (p < 0.01) liver concentrations of C18:1 n-9, C18:2 n-6, and arachidonic acid, the fish-oil-supplemented cattle had greater (p < 0.01) concentrations of liver EPA, DHA, and C18:3 n-3. In the brain, DHA was the most abundant polyunsaturated fatty acid. In the amygdala, pons, frontal lobe, internal capsule, and sensory cortex, DHA concentrations were greater (p < 0.05) in the brains of the cattle fed fish oil. Differences among the supplements were small, indicating that brain DHA content is resistant to dietary change. Arachidonic acid and C22:4 n-6 concentrations were greater across the regions for the palm-oil-supplemented cattle. EPA and C22:5 n-3 concentrations were low, but they were greater across the regions for the cattle fed fish oil. The effects of sex were inconsistent. The fatty acid profiles of the brain regions differed by diet, but they were similar to the contents reported for other species.

OBJECTIVE:Food-seeking behaviors can be driven by food-associated cues, and palatable food seeking in response to food cues is a risk factor for obesity development. Cue-induced food seeking increases following a period of abstinence, a behavioral phenomenon known as "incubation of craving," which may contribute to an individual's difficulty abstaining from palatable foods. Pharmacological and environmental manipulations have been employed to try and reduce incubation of craving, albeit primarily in drug abuse paradigms. The goal of this study was to determine whether forced exercise can attenuate incubation of high-fat food craving.METHODS:Male Sprague Dawley rats learned to self-administer high-fat pellets (60%) in combination with a compound cue (light + tone). The influence of high-intensity interval exercise on the time-dependent increase in cue-induced lever responding was investigated 30 days after the first cue test.RESULTS:Rats exposed to exercise during abstinence did not express incubation of craving.CONCLUSIONS:The results suggest that high-intensity exercise can prevent the establishment of incubation of craving for foods high in fat and may reduce cue-induced maladaptive food-seeking behaviors that contribute to overeating and obesity.

Sex differences in motivation for food rewards, gambling, and drugs of abuse are modulated by multiple factors, including sensory stimuli, gonadal hormones, and cognitive bias. Cues, drugs of abuse, and a high-fat diet can significantly impact neural signaling in the reward system and functioning of neural systems that regulate executive functions differentially in males and females. Additionally, sex differences in risky decision-making, cognitive bias, and motivation for food and drugs of abuse are mediated by gonadal hormones in both sexes. As neuroscientists analyze data from both sexes, it is becoming apparent that these differences are not simply mediated by hormones in females, but involve sex differences in the specific neural responses to stimuli, including both external stimuli and internal hormonal signals. Understanding sex differences in the mechanisms underlying reward-seeking behaviors and the development of substance use disorders will help uncover potential therapies and treatments that will benefit both men and women. Based on these observations, it is essential that females are included in neuroscience research.

Overindulgence, excessive consumption, and a pattern of compulsive use of natural rewards, such as certain foods or drugs of abuse, may result in the development of obesity or substance use disorder, respectively. Natural rewards and drugs of abuse can trigger similar changes in the neurobiological substrates that drive food- and drug-seeking behaviors. This review examines the impact natural rewards and drugs of abuse have on perineuronal nets (PNNs). PNNs are specialized extracellular matrix structures that ensheathe certain neurons during development over the critical period to provide synaptic stabilization and a protective microenvironment for the cells they surround. This review also analyzes how natural rewards and drugs of abuse impact the density and maturation of PNNs within reward-associated circuitry of the brain, which may contribute to maladaptive food- and drug-seeking behaviors. Finally, we evaluate the relatively few studies that have degraded PNNs to perturb reward-seeking behaviors. Taken together, this review sheds light on the complex way PNNs are regulated by natural rewards and drugs and highlights a need for future studies to delineate the molecular mechanisms that underlie the modification and maintenance of PNNs following exposure to rewarding stimuli.

Persistent/chronic inflammatory pain involves multiple pathophysiological mechanisms and is far more complex than acute/momentary pain. Current therapeutics for chronic inflammatory pain are often not effective because the etiology responsible for the pain is not addressed by traditional pharmacological treatments. Cathepsin K is a cysteine protease that has mostly been studied in the context of bone and joint disorders. Previous work by others has shown that inhibition of cathepsin K activity reduces osteoarthritis-associated nociception in joints. However, the role of cathepsin K in cutaneous inflammation is understudied. We assessed the effectiveness of genetic deletion or pharmacological inhibition of cathepsin K in male mice on the expression of nocifensive behaviors after formalin injection or mechanical and thermal hypersensitivity after injection of complete Freund’s adjuvant (CFA) into the mouse hind paw. Our data demonstrate that cathepsin K knockout mice ( Ctsk −/− ) have a reduction in nocifensive behaviors in the formalin test. In addition, Ctsk −/− do not develop mechanical hypersensitivity after CFA injection for up to 7 days. Moreover, we found that inhibition of cathepsin K reduced mechanical hypersensitivity after CFA injection and mRNA levels, protein levels, and cathepsin K activity levels were elevated after CFA injection. Based upon our data, cathepsin K is indicated to play a role in the expression of chemically-induced cutaneous hypersensitivity, as Ctsk −/− mice do not develop mechanical hypersensitivity and show a reduction in nocifensive behaviors. Further research is needed to determine whether attenuating cathepsin K activity may generate a clinically relevant therapeutic.

Perineuronal nets (PNNs) surrounding fast-spiking, parvalbumin (PV) interneurons provide excitatory:inhibitory balance, which is impaired in several disorders associated with altered diurnal rhythms, yet few studies have examined diurnal rhythms of PNNs or PV cells. We measured the intensity and number of PV cells and PNNs labeled with Wisteria floribunda agglutinin (WFA) and also the oxidative stress marker 8-oxo-deoxyguanosine (8-oxo-dG) in rat prelimbic medial prefrontal cortex (mPFC) at Zeitgeber times (ZT) ZT0 (lights-on, inactive phase), ZT6 (mid-inactive phase), ZT12 (lights-off, active phase), and ZT18 (mid-active phase). Relative to ZT0, the intensities of PNN and PV labeling were increased in the dark (active) phase compared with the light (inactive) phase. The intensity of 8-oxo-dG was decreased from ZT0 at all times (ZT6,12,18). We also measured GAD 65/67 and vGLUT1 puncta apposed to PV cells with and without PNNs. There were more excitatory puncta on PV cells with PNNs at ZT18 vs. ZT6, but no changes in PV cells without PNNs and no changes in inhibitory puncta. Whole-cell slice recordings in fast-spiking (PV) cells with PNNs showed an increased ratio of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor:N-methyl-D-aspartate receptor (AMPA: NMDA) at ZT18 vs. ZT6. The number of PV cells and PV/PNN cells containing orthodenticle homeobox 2 (OTX2), which maintains PNNs, showed a strong trend toward an increase from ZT6 to ZT18. Diurnal fluctuations in PNNs and PV cells are expected to alter cortical excitatory:inhibitory balance and provide new insights into treatments for diseases impacted by disturbances in sleep and circadian rhythms.

Perineuronal nets (PNNs) are specialized extracellular matrix structures that primarily surround fast-spiking parvalbumin (PV)-containing interneurons within the PFC. They regulate PV neuron function and plasticity to maintain cortical excitatory/inhibitory balance. For example, reductions in PNN intensity are associated with reduced local inhibition and enhanced pyramidal neuron firing. We previously found that exposure to dietary high fat reduced PNN intensity within the PFC of male Sprague-Dawley (SD) rats. However, how high fat affects PNNs in the PFC of females or in obesity-vulnerable vs. -resistant models is unknown. Therefore, we gave male and female SD, selectively bred obesity-prone (OP), and obesity-resistant rats (OR) free access to standard lab chow or 60% high fat for 21 days. We then measured the number of PNN positive cells and PNN intensity (determined by Wisteria floribunda agglutinin [WFA] staining) as well as the number of PV positive neurons using immunohistochemistry. We found sex and region-specific effects of dietary high fat on PNN intensity, in the absence of robust changes in cell number. Effects were comparable in SD and OP but differed in OR rats. Specifically, high fat reduced PNN intensities in male SD and OP rats but increased PNN intensities in female SD and OP rats. In contrast, effects in ORs were opposite, with males showing increases in PNN intensity and females showing a reduction in intensity. Finally, these effects were also region specific, with diet-induced reductions in PNN intensity found in the prelimbic PFC (PL-PFC) and ventral medial orbital frontal cortex (vmOFC) of SD and OP males in the absence of changes in the infralimbic PFC (IL-PFC), and increases in PNN intensity in the IL-PFC of SD and OP females in the absence of changes in other regions. These results are discussed in light of roles PNNs may play in influencing PFC neuronal activity and the differential role of these sub-regions in food-seeking and motivation.

Substance use disorder is a complex disease created in part by maladaptive learning and memory mechanisms following repeated drug use. Exposure to drug-associated stimuli engages prefrontal cortex circuits, and dysfunction of the medial prefrontal cortex (mPFC) is thought to underlie drug-seeking behaviors. Growing evidence supports a role for parvalbumin containing fast-spiking interneurons (FSI) in modulating prefrontal cortical microcircuit activity by influencing the balance of excitation and inhibition, which can influence learning and memory processes. Most parvalbumin FSIs within layer V of the prelimbic mPFC are surrounded by specialized extracellular matrix structures called perineuronal nets (PNN). Previous work by our group found that cocaine exposure altered PNN-surrounded FSI function, and pharmacological removal of PNNs reduced cocaine-seeking behavior. However, the role of FSIs and associated constituents (parvalbumin and PNNs) in cocaine-related memories was not previously explored and is still unknown. Here, we found that reactivation of a cocaine conditioned place preference memory produced changes in cortical PNN-surrounded parvalbumin FSIs, including decreased parvalbumin intensity, increased parvalbumin cell axis diameter, decreased intrinsic excitability, and increased excitatory synaptic input. Further investigation of intrinsic properties revealed changes in the interspike interval, membrane capacitance, and afterhyperpolarization recovery time. Changes in these specific properties suggest an increase in potassium-mediated currents, which was validated with additional electrophysiological analysis. Collectively, our results indicate that cocaine memory reactivation induces functional adaptations in PNN-surrounded parvalbumin neurons, which likely alters cortical output to promote cocaine-seeking behavior.

CP-AMPARs in the nucleus accumbens (NAc) mediate cue-triggered motivation for food and cocaine. In addition, increases in NAc CP-AMPAR expression and function can be induced by cocaine or sugary, fatty junk-foods. However, the precise nature of these alterations and the degree to which they rely on the same underlying mechanisms is not well understood. This has important implications for understanding adaptive vs. maladaptive plasticity that drives food- and drug-seeking behaviors. Furthermore, effects of junk-foods on glutamatergic plasticity in females are unknown. Here, we use a combination of protein biochemistry and whole-cell patch clamping to determine effects of diet manipulation on glutamatergic plasticity within the NAc of males and females. We found that junk-food consumption increases silent synapses and subsequently increases CP-AMPAR levels in males in the NAc of male rats. In addition, a brief period of junk-food deprivation is needed for the synaptic insertion of CP-AMPARs and the maturation of silent synapses in males. In contrast, junk-food did not induce AMPAR plasticity in females but may instead alter NMDAR-mediated transmission. Thus, these studies reveal sex differences in the effects of junk-food on NAc synaptic plasticity. In addition, they provide novel insights into how essential food rewards alter NAc function.

Perineuronal nets (PNNs) are specialized extracellular matrix structures that ensheathe parvalbumin-containing fast-spiking interneurons (PV FSIs) and play a key role in neuroplasticity. We previously showed that PNNs within the prelimbic prefrontal cortex (PL PFC) are required for the maintenance of cocaine-associated memories following cocaine memory reactivation. However, how cocaine memory reactivation affects PNNs, PV, and corresponding changes in PV FSI function are unknown. In this study, we characterized the electrophysiological properties of PV FSIs and corresponding changes in PNN and PV intensity within the PL PFC prior to and after cocaine memory reactivation. Adult male Sprague-Dawley rats were trained to acquire cocaine-conditioned place preference (CPP) and, following cocaine-CPP memory reactivation (30 m, 2 h, and 24 h post-reactivation), we measured PNN intensity (determined by Wisteria floribunda agglutinin [WFA] staining) as well as PV intensity using immunohistochemistry. The intensity of PV staining was reduced at all time points following memory reactivation with no changes in WFA intensity. Using whole-cell electrophysiology we found a reduction in the number of action potentials at 30 m and 2 h that returned to control levels by 24 h. The attenuation in firing was accompanied by a presumed compensatory increase in excitatory synaptic transmission, which was corroborated by an increase in VGluT1 puncta apposing PV/PNN neurons. Collectively, our results indicate that cocaine memory reactivation decreases PV intensity, which may play a role in decreasing excitation of PV FSIs. Thus, the inhibitory tone onto pyramidal neurons may be decreased following memory reactivation, resulting in an increase in PFC output to promote cocaine-seeking behaviors.