Accumbens Research Articles

Dopamine D3 receptor mediates natural and methamphetamine rewards via regulating the expression of miR-29c in the nucleus accumbens of mice

The dopamine D3 receptor (D3R), principally confined to the nucleus accumbens (NAc), is involved in regulating natural and drug rewards; however, the molecular mechanisms underlying the associated process remain unclear. Earlier research has reported the concurrent influence of D3R and miR-29c expressed in the NAc on methamphetamine (METH)-induced reward behaviors and microglial activation, hinting at regulatory roles in reward processing. Herein, we performed viral manipulation-mediating D3R/miR-29c overexpression and inhibition in the whole NAc in male D3R knockout and wild-type mice to investigate this potential relationship. Behavioral responses to the rewarding stimuli were assessed using sucrose preference score, METH-induced locomotor sensitization, and METH-induced conditioned place preference tests. Overall, we observed a notable decrease in the behavioral response to sucrose and METH in D3R-deficient mice, accompanied by the downregulation of miR-29c expression in the NAc. Diminished responses to those rewarding stimuli in D3R-deficient mice primarily stemmed from the reduction of GSK3β activity and subsequent down-regulation of miR-29c in the NAc. Microglial activation in the NAc mediates the effect of D3R-miR-29c deficiency on the reward effects of sucrose and METH. Pharmacological suppression of microglial activity rescued the reduced response in mice lacking D3R-miR-29c in the NAc. Overall, this study revealed the mechanism by which D3R regulates both natural and drug rewards via miR-29c in the murine NAc, highlighting the role of the NAc D3R-miR-29c pathway as a critical regulator of rewards, and providing new insights into the role of NAc D3R-miR-29c in encoding rewarding experiences.

LASP1 in the nucleus accumbens modulates methamphetamine-induced conditioned place preference in mice

Methamphetamine (METH) is a highly addictive and widely abused drug that causes complex adaptive changes in the brain’s reward system, such as the nucleus accumbens (NAc). LASP1 (LIM and SH 3 domain protein 1) as an actin-binding protein, regulates synaptic plasticity. However, the role and mechanism by which NAc LASP1 contributes to METH addiction remains unclear. In this study, adult male C57BL/6J mice underwent repeated METH exposure or METH-induced conditioned place preference (CPP). Western blotting and immunohistochemistry were used to determine LASP1 expression in the NAc. Furthermore, LASP1 knockdown or overexpression using adeno-associated virus (AAV) administration via stereotactic injection into the NAc was used to observe the corresponding effects on CPP. We found that repeated METH exposure and METH-induced CPP upregulated LASP1 expression in the NAc. LASP1 silencing in the NAc reversed METH-induced CPP and reduced PSD95, NR2A, and NR2B expression, whereas LASP1 overexpression in the NAc enhanced CPP acquisition, accompanied by increased PSD95, NR2A, and NR2B expression. Our findings demonstrate an important role of NAc LASP1 in modulating METH induced drug-seeking behavior and the underlying mechanism may be related to regulate the expression of synapse-associated proteins in the NAc. These results reveal a novel molecular regulator of the actions of METH on the NAc and provide a new strategy for treating METH addiction.

Comparison of Resting-State Functional Connectivity Between Generalized Anxiety Disorder and Social Anxiety Disorder: Differences in the Nucleus Accumbens and Thalamus Network.

Background: Generalized anxiety disorder (GAD) and social anxiety disorder (SAD) are distinguished by whether anxiety is limited to social situations. However, reports on the differences in brain functional networks between GAD and SAD are few. Our objective is to understand the pathogenesis of GAD and SAD by examining the differences in resting brain function between patients with GAD and SAD and healthy controls (HCs). Methods: This study included 21 patients with SAD, 17 patients with GAD, and 30 HCs. Participants underwent psychological assessments and resting-state functional magnetic resonance imaging. Whole-brain analyses were performed to compare resting-state functional connectivity (rsFC) among the groups. In addition, logistic regression analysis was conducted on the rsFC to identify significant differences between GAD and SAD. Results: Patients with SAD and GAD had significantly higher rsFC between the bilateral postcentral gyri and bilateral amygdalae/thalami than HCs. Compared with patients with SAD, those with GAD had significantly higher rsFC between the right nucleus accumbens and bilateral thalami and between the left nucleus accumbens and right thalamus. rsFC between the left nucleus accumbens and right thalamus positively correlated with state anxiety in patients with SAD and GAD, respectively. In addition, logistic regression analysis revealed that the right nucleus accumbens and the right thalamus connectivity could distinguish SAD from GAD. Conclusions: GAD and SAD were distinguished by the right nucleus accumbens and the right thalamus connectivity. Our findings offer insights into the disease-specific neural basis of SAD and GAD. Clinical Trial Registration Number: UMIN000024087. Impact Statement This study is the first to identify a resting state functional connectivity that distinguishes social anxiety disorder (SAD) from generalized anxiety disorder (GAD) and to clarify a common connectivity in both disorders. We found that the connectivity between the right nucleus accumbens and the right thalamus differentiated SAD from GAD. Furthermore, these rsFC differences suggest an underlying basis for fear overgeneralization. Our findings shed light on the pathophysiology of these conditions and could be used as a basis for further studies to improve outcomes for such patients.

Stimulation of kappa opioid receptors in the nucleus accumbens promotes feeding behavior in mice: Acute restoration of feeding during anorexia induced by 5-fluorouracil

Though μ and δ opioid receptors are reported to regulate energy homeostasis, any role for κ opioid receptors in these processes remains unclear. The present study investigated the role of κ opioid receptors in regulation of feeding behavior and plasma glucose levels using nalfurafine, a κ opioid receptor agonist used clinically. Systemic injection of nalfurafine increased food intake under non-fasted conditions, but not after food deprivation, and this effect was inhibited by the κ opioid receptor antagonist norbinaltorphimine. In contrast, nalfurafine did not affect plasma glucose levels. I.c.v. injection of nalfurafine increased food intake, whereas systemic injection of nalfurafine methiodide, which does not penetrate the blood brain barrier, was without effect. In addition, nalfurafine tended to increase preproorexin mRNA in the hypothalamus. However, neither the orexin OX1 receptor antagonist YNT-1310 nor the non-selective orexin receptor antagonist suvorexant inhibited the increase in food intake induced by nalfurafine. While nalfurafine injected into the lateral hypothalamus did not affect food intake, nalfurafine injected into the nucleus accumbens increased food intake, which was inhibited by norbinaltorphimine. Finally, we examined the effect of nalfurafine on anorexia induced by the anti-cancer agent 5-fluorouracil. Reduced food intake at 2 days following 5-fluorouracil administration was alleviated across the first 3 h following daily injection of nalfurafine, though daily food intake was not influenced. These results indicate that nalfurafine promotes feeding behavior through stimulation of κ opioid receptors in the nucleus accumbens and may be a candidate for reducing anorexia due to anti-cancer agents.

Apathy and effort-based decision-making in Alzheimer's disease and subjective cognitive impairment.

Apathy is a significant feature in Alzheimer's disease (AD) and subjective cognitive impairment (SCI), though its mechanisms are not well established. An effort-based decision-making (EBDM) framework was applied to investigate apathy in 30 AD patients, 41 SCI participants, and 55 healthy controls (HC). Data were analyzed using a drift-diffusion model (DDM) to uncover latent psychological processes. SCI participants reported higher apathy than AD patients and HC. However, informant reports of apathy in AD patients were higher than self-reports and indicated significant apathy compared to HC. Both the AD and SCI groups showed reduced sensitivity to effort changes, linked to executive dysfunction in AD and apathy in SCI. Increased resting functional cortical connectivity with the nucleus accumbens (NA) was associated with higher apathy in SCI. These results highlight a similar disruption of EBDM in AD and SCI, differentially related to executive functioning in AD and apathy in SCI. This is the first study investigating apathy using an effort-based decision-making (EBDM) framework in Alzheimer's disease (AD) and subjective cognitive impairment (SCI).Self-reports underestimate apathy in AD patients when compared to informant reports and healthy controls (HC). SCI participants, in whom self and informant reports were more concordant, also showed higher degrees of apathy.Both AD and SCI groups showed reduced sensitivity to effort.Reduced sensitivity to effort correlates with executive dysfunction in AD and apathy, but not depression, in SCI.Increased nucleus accumbens (ventral striatum) connectivity with the frontoparietal network was associated with higher apathy scores in SCI.The results thus suggest that while AD and SCI can have similar deficits in EBDM, these deficits correlate with distinct clinical manifestations: executive dysfunction in AD and apathy in SCI.

Mild forced exercise in young mice prevents anergia induced by dopamine depletion in late adulthood: Relation to CDNF and DARPP-32 phosphorylation patterns in nucleus accumbens

Mesolimbic dopamine (DA) plays a critical role in behavioral activation and exertion of effort in motivated behaviors. DA antagonism and depletion in nucleus accumbens (Nacb) induces anergia in effort-based decision-making tasks. Exercise improves motor function in Parkinson's disease (PD). However, the beneficial effects of physical exercise on anergia, a symptom present in many psychiatric and neurological pathologies needs to be studied. During 9 weeks, young CD1 male mice were trained to run at a moderate speed in automatically turning running wheels (RW) (forced exercise group) or locked in static RWs (control group) in 1 h daily sessions. Both groups were tested in a 3-choice-T-maze task developed for the assessment of preference between active (RW) vs. sedentary reinforcers, and vulnerability to DA depletion-induced anergia was studied after tetrabenazine administration (TBZ; VMAT-2 blocker). Exercise did not change spontaneous preferences, did not affect body weight, plasma corticosterone levels or measures of anxiety, but it increased the cerebral DA neurotrophic factor (CDNF) in Nacb core, suggesting a neuroprotective effect in this nucleus. After TBZ administration, only the non-trained group showed a shift in relative preferences from active to sedentary options, reducing time running but increasing consumption of pellets, thus showing a typical anergic but not anhedonic effect. Moreover, only in the non-trained group, phosphorylation of DARPP-32(Thr34) increased after TBZ administration. These results are the first to show that mild forced exercise carried out from a young age to adulthood could act on Nacb-related functions, and prevent the anergia-inducing effects of DA depletion.

Astrocytic CREB in nucleus accumbens promotes susceptibility to chronic stress

BackgroundIncreasing evidence implicates astrocytes in stress and depression in both rodent models and human Major Depressive Disorder (MDD). Despite this, little is known about the transcriptional responses to stress of astrocytes within the nucleus accumbens (NAc), a key brain reward region, and their influence on behavioral outcomes. MethodsWe used whole cell sorting, RNA-sequencing, and bioinformatic analyses to investigate the NAc astrocyte transcriptome in male mice in response to chronic social defeat stress (CSDS). Immunohistochemistry was used to determine stress-induced changes in astrocytic CREB within the NAc. Finally, astrocytic regulation of depression-like behavior was investigated using viral-mediated manipulation of CREB in combination with CSDS. ResultsWe found a robust transcriptional response in NAc astrocytes to CSDS in stressed mice, with changes seen in both stress-susceptible and stress-resilient animals. Bioinformatic analysis revealed CREB, a transcription factor widely studied in neurons, as one of the top-predicted upstream regulators of the NAc astrocyte transcriptome, with opposite activation states implicated in resilient vs. susceptible mice. This bioinformatic deduction was confirmed at the protein level with immunohistochemistry. Moreover, NAc astrocyte morphological complexity correlated with CREB activation and was reduced selectively in astrocytes of resilient mice. Viral overexpression of CREB selectively in NAc astrocytes promoted susceptibility to chronic stress. ConclusionsTogether, our data demonstrate that the astrocyte transcriptome responds robustly to CSDS and that transcriptional regulation in astrocytes contributes to depressive-like behaviors. A better understanding of transcriptional regulation in astrocytes may reveal unknown molecular mechanisms underlying neuropsychiatric disorders.

Sex-Dependent Synergism of an Edible THC: CBD Formulation in Reducing Anxiety and Depressive-like Symptoms Following Chronic Stress.

Cannabis has shown therapeutic potential in mood and anxiety-related pathologies. However, the two primary constituents of cannabis, cannabidiol (CBD) and Δ-9-tetrahydrocannabinol (THC) produce distinct effects on molecular pathways in neural circuits associated with affective disorders. Moreover, it has been proposed that the combination of THC: and CBD may have unique synergistic properties. In the present study, the effects of a 1:100 THC: CBD ratio edible formulation were tested in behavioural, neuronal and molecular assays for anxiety and depressive-like endophenotypes. Adult male and female Sprague-Dawley rats were stressed for 14 days. Then, for three weeks, open field, elevated plus maze, light/dark box, social interaction, sucrose preference, and the forced swim test were performed 90 minutes after acute consumption of CBD (30 mg/kg), THC (0.3 mg/kg), or 1:100 combination of THC:CBD. After behavioural tests, in vivo, neuronal electrophysiological analyses were performed in the ventral tegmental area and prefrontal cortex (PFC). Furthermore, western-blot experiments examined the expression of biomarkers associated with mood and anxiety disorders, including protein kinase B (Akt), glycogen synthase kinase-3 (GSK-3), BDNF, mTOR, D1, and D2 receptor in nucleus accumbens (NAc) and PFC.Edible THC:CBD produces significant anxiolytic and antidepressant effects only in stressed male rats. In most cases, the combination of THC and CBD had stronger effects than either phytochemical alone. These synergistic effects are associated with alterations in Akt/GSK3 and D2-R expression in NAc and BDNF expression in PFC. Furthermore, THC:CBD reverses chronic stress-induced alterations in PFC neuronal activity. These findings demonstrate a novel synergistic potential for THC:CBD edible formulations in stress-related pathologies.

Neural and molecular investigation into the paraventricular thalamus for chronic restraint stress induced depressive-like behaviors

IntroductionDisturbance of neural circuits and chronic stress contribute to depression onset. Given the crucial role of paraventricular nucleus of thalamus (PVT) in emotional behaviors, however, the specific neural and molecular mechanism of PVT in depression still unclear. ObjectiveOur study aim to explore the neural and molecular mechanism of PVT in depression. MethodsIn the present study, we utilize behavioral tests,chemogenetics, RNA-sequence, molecular profiling and pharmacological approaches to investigate the role of PVT in depression. ResultsWe observed that CamkIIα neurons in PVT were inactivated by chronic restraint stress (CRS) with reduced c-Fos positive neurons. Activation of PVTCamkIIα neurons displayed antidepressant-like effect in both naive and CRS mice, whereas inhibition or ablation of these neurons is sufficient to trigger depressive-like behaviors. Moreover, we found that activating PVT → Nucleus accumbens (NAc) circuit attenuated depressive-like behaviors induced by CRS, while inhibiting this circuit directly caused behavioral deficits in mice. Intriguingly, artificially enhancing PVT → Central amygdala (CeA) pathway failed to alleviate depressive-like behaviors. Importantly, increased expression of neuropeptide Y (NPY) and depressive-like behaviors induced by CRS could be ameliorated via antidepressant treatment, manipulation of PVTCamkIIα neurons (or PVT → NAc circuit) and NPY inhibitor. ConclusionTaken together, our study uncovered that PVT regulated depressive-like behaviors via PVT → NAc circuit together with NPY, thus shedding light on potential target for preventing depression and promoting clinical translation.

Genome-wide association study meta-analysis of 9,619 cases with tic disorders

Despite the significant personal and societal burden of tic disorders (TD), treatment outcomes remain modest, necessitating a deeper understanding of their etiology. Family history is the biggest known risk factor and identifying risk genes could accelerate progress in the field. Expanding upon previous sample size limitations, we added 4,800 new TD cases and 971,560 controls, conducting a GWAS meta-analysis with 9,619 cases and 981,048 controls of European ancestry. We attempted to replicate the results in an independent deCODE Genetics GWAS (885 TD cases and 310,367 controls). To characterize GWAS findings, we conducted several post-GWAS gene-based and enrichment analyses. A genome-wide significant hit (rs79244681, p=2.27x10-08) within MCHR2-AS1 was identified, though it was not replicated. Post-GWAS analyses revealed a 13.8% SNP-heritability and three significant genes: BCL11B, NDFIP2, and RBM26. Common variant risk for TD was enriched within genes preferentially expressed in the cortico-striato-thalamo-cortical circuit (including the putamen, caudate, nucleus accumbens, and Brodman area 9) and five brain cell types (excitatory and inhibitory telencephalon-, inhibitory- di- and mesencephalon, hindbrain-, and medium spiny neurons). TD polygenic risk was enriched within loss-of-function intolerant genes (p=0.0017) and high-confidence neurodevelopmental disorder genes (p=0.0108). Of 112 genetic correlations, 43 were statistically significant, showing high positive correlations with most psychiatric disorders. Of the two SNPs previously associated with TD, one (rs2453763) replicated in an independent sub-sample of our GWAS (p=0.00018). This GWAS was still underpowered to identify high-confidence, replicable loci, but the results suggest imminent discovery of common genetic variants for TD.

Examining the effects of the HIV-1 protein Tat and morphine on antiretroviral accumulation and distribution within the brain.

Despite combination antiretroviral therapy effectively suppressing HIV within the periphery, neuro-acquired HIV (neuroHIV) remains a significant problem and approximately half of people living with HIV will experience HIV-associated neurocognitive disorders (HAND). Concurrent opioid use exacerbates neuroHIV by promoting neuroinflammation, neuronal injury and synaptodendritic culling, viral replication, and potentially altering antiretroviral concentrations within the brain. The present study examined the effects of HIV and morphine co-exposure on the accumulation and spatial distribution of antiretroviral drugs across multiple regions within the brain in an HIV-1 Tat transgenic mouse model by using infrared-matrix-assisted laser desorption electrospray ionization mass spectrometry imaging (IR-MALDESI MSI). Morphine exposure uniquely decreased antiretroviral concentrations in anterior cerebral (primary motor and somatosensory) cortices, corpus collosum (anterior forceps), caudoputamen, nucleus accumbens, and posterior regions including the hippocampus, corpus callosum (main body), cerebral cortex (somatosensory and auditory cortices), thalamus, and hypothalamus. Interestingly, male mice experienced greater morphine-associated decreases in antiretroviral concentrations than females. The study also assessed whether changes in antiretroviral concentrations were linked with inflammation in astroglia, assessed through the measurement of astroglial activation using glial fibrillary acidic protein (GFAP) as a marker. Alterations in antiretroviral concentrations co-registering with areas of astroglial activation exhibited sex-specific treatment differences. This study highlights the intricate interplay between HIV, opioids, and antiretroviral drugs within the CNS, elucidating distinct regional and sex variations in responsiveness. Our findings emphasize the identification of vulnerabilities within the neural landscape and underscore the necessity of carefully monitoring opioid use to maintain the efficacy of antiretroviral therapies.

Replication and extension of the subregion selectivity of glutamate-related changes within the nucleus accumbens associated with the incubation of cocaine-craving

Cue-elicited drug-seeking behavior intensifies with the passage of time during withdrawal from drug taking and this “incubation of cocaine-craving” involves alterations in nucleus accumbens (NA) glutamate transmission. Here, we employed a combination of in vivo microdialysis and immunoblotting approaches to further examine changes in biochemical indices of glutamate transmission within NA subregions that accompany the incubation of cocaine-craving exhibited by male rats with a 10-day history of 6-h access to intravenous cocaine (0.25 mg/infusion). Immunoblotting on whole cell lysates from the core subregion (NAc core) revealed interactions between cocaine self-administration history, withdrawal and drug cue re-exposure for Homer2a/b, mGlu1, and GluN2b expression, as well as indices of Akt and ERK activity. With the exception of PKCε phosphorylation, most protein changes within the shell subregion (NAc shell) depended on drug cue re-exposure and cocaine history rather than varying in a consistent time-dependent manner. Reduced basal extracellular glutamate content was apparent only in the NAc core of cocaine-experienced rats during protracted (30 days) withdrawal and this was accompanied by a markedly blunted capacity of the mGlu1/5 agonist DHPG to elevate glutamate levels within this subregion. Finally, over-expressing neither Homer1c nor Homer2b within the NAc core during protracted cocaine withdrawal altered the magnitude of cue-elicited responding, its extinction or cocaine-primed reinstatement of drug-seeking behavior. The present findings are consistent with the extant literature implicating changes in Group 1 mGlu receptor function within the NAc core subregion as central to incubated cocaine-craving and provide further evidence against a major role for Homer proteins in gating incubated cocaine-craving. Further, our results provide novel correlational evidence implicating elevated Akt and blunted ERK activity within the NAc core as potential contributors to the expression of incubated cocaine-craving, worthy of future investigation.

Microdosing of a kappa opioid receptor agonist within proximal nucleus accumbens shell microstructures revealing opposing behavioral outcomes

Targeted intracranial delivery of molecularly-specific therapies within intricate brain structures poses a formidable challenge due to the heterogeneity of neuronal phenotypes and functions. Here we report the use of an implantable, miniaturized neural drug delivery system permitting dynamic adjustment of pharmacotherapies. Specifically, we exploit the spatial accuracy afforded by this method for targeting modulation of neuronal microstructures. Kappa opioid receptors (KOR) within the dorsal medial nucleus accumbens shell (NASh) are selectively activated through micro infusions of the KOR agonist, U-50488. Remarkably, we demonstrate that micro infusions of U-50488 into the dorsal NASh induces reward-like conditioned place preferences, whereas a mere 1 mm shift ventrally results in conditioned place aversions. The striking precision afforded by this method may prove useful in other neurotherapeutic interventions.

Activation of the nucleus accumbens promotes place preference and counteracts stress-induced hyperthermia.

Activation of the nucleus accumbens promotes place preference and counteracts stress-induced hyperthermia.

Role of the Nucleus Accumbens in Signaled Avoidance Actions.

Animals, humans included, navigate their environments guided by sensory cues, responding adaptively to potential dangers and rewards. Avoidance behaviors serve as adaptive strategies in the face of signaled threats, but the neural mechanisms orchestrating these behaviors remain elusive. Current circuit models of avoidance behaviors indicate that the nucleus accumbens (NAc) in the ventral striatum plays a key role in signaled avoidance behaviors, but the nature of this engagement is unclear. Evolving perspectives propose the NAc as a pivotal hub for action selection, integrating cognitive and affective information to heighten the efficiency of both appetitive and aversive motivated behaviors. To unravel the engagement of the NAc during active and passive avoidance, we used calcium imaging fiber photometry to examine NAc GABAergic neuron activity in ad libitum moving mice performing avoidance behaviors. We then probed the functional significance of NAc neurons using optogenetics and genetically targeted or electrolytic lesions. We found that NAc neurons code contraversive orienting movements and avoidance actions. However, direct optogenetic inhibition or lesions of NAc neurons did not impair active or passive avoidance behaviors, challenging the notion of their purported pivotal role in adaptive avoidance. The findings emphasize that while the NAc encodes avoidance movements, it is not required for avoidance behaviors, highlighting the distinction between behavior encoding or representation and mediation or generation.

Codes between Poles: Linking Transcriptomic Insights into the Neurobiology of Bipolar Disorder.

Bipolar disorder (BPD) is a serious psychiatric condition that is characterized by the frequent shifting of mood patterns, ranging from manic to depressive episodes. Although there are already treatment strategies that aim at regulating the manifestations of this disorder, its etiology remains unclear and continues to be a question of interest within the scientific community. The development of RNA sequencing techniques has provided newer and better approaches to studying disorders at the transcriptomic level. Hence, using RNA-seq data, we employed intramodular connectivity analysis and network pharmacology assessment of disease-associated variants to elucidate the biological pathways underlying the complex nature of BPD. This study was intended to characterize the expression profiles obtained from three regions in the brain, which are the nucleus accumbens (nAcc), the anterior cingulate cortex (AnCg), and the dorsolateral prefrontal cortex (DLPFC), provide insights into the specific roles of these regions in the onset of the disorder, and present potential targets for drug design and development. The nAcc was found to be highly associated with genes responsible for the deregulated transcription of neurotransmitters, while the DLPFC was greatly correlated with genes involved in the impairment of components crucial in neurotransmission. The AnCg did show association with some of the expressions, but the relationship was not as strong as the other two regions. Furthermore, disease-associated variants or single nucleotide polymorphisms (SNPs) were identified among the significant genes in BPD, which suggests the genetic interrelatedness of such a disorder and other mental illnesses. DRD2, GFRA2, and DCBLD1 were the genes with disease-associated variants expressed in the nAcc; ST8SIA2 and ADAMTS16 were the genes with disease-associated variants expressed in the AnCg; and FOXO3, ITGA9, CUBN, PLCB4, and RORB were the genes with disease-associated variants expressed in the DLPFC. Aside from unraveling the molecular and cellular mechanisms behind the expression of BPD, this investigation was envisioned to propose a new research pipeline in studying the transcriptome of psychiatric disorders to support and improve existing studies.

Enhancing chronic low back pain management: an initial neuroimaging study of a mobile interoceptive attention training.

Chronic low back pain (cLBP) poses significant challenges, often addressed through avoidance or distraction. Emerging evidence suggests that mind-body interventions, like our novel Mind Your Pain (MyP) smartphone mobile application, may offer relief. We conducted a single-arm, mixed-methods neuroimaging study to assess the degree to which treatment response to our 8-week intervention, as measured by the reduction in the Pain, Enjoyment of Life and General Activity Scale (PEG), was associated with enhanced pain-related insula activation over time. Twenty-nine individuals with cLBP completed patient-reported assessments, qualitative sensory testing (QST) measures, and neuroimaging pre- and post-MyP. Functional MRI data during experimental heat pain on the left forearm were collected and analyzed, comparing responders (≥50% reduction in PEG scores) and non-responders. MyP led to significant decreases in PEG scores overall. Furthermore, MyP responders exhibited increased pain-related activation in key brain regions, including the contralateral posterior insula, bilateral ventral anterior insula, ventral anterior cingulate, dorsolateral prefrontal cortex, and nucleus accumbens. Although baseline behavioral and sensory measures did not differ between the two responder groups, baseline neural differences related to the impact of the endogenous back pain were observed. MyP appears to modify pain response and underlying neural circuitry, suggesting neural changes in interoception may serve as biomarkers for mind-body interventions in cLBP. This study highlights the potential of MyP as a novel approach for cLBP management, warranting further investigation.

The Influence of Strain and Sex on High Fat Diet-Associated Alterations of Dopamine Neurochemistry in Mice.

Objective: The objective of this study was to determine the influence of sex and strain on striatal and nucleus accumbens dopamine neurochemistry and dopamine-related behavior due to a high-saturated-fat diet (HFD). Methods: Male and female C57B6/J (B6J) and Balb/cJ (Balb/c) mice were randomly assigned to a control-fat diet (CFD) containing 10% kcal fat/g or a mineral-matched HFD containing 60% kcal fat/g for 12 weeks. Results: Intraperitoneal glucose tolerance testing (IPGTT) and elevated plus maze experiments (EPM) confirmed that an HFD produced marked blunting of glucose clearance and increased anxiety-like behavior, respectively, in male and female B6J mice. Electrically evoked dopamine release in the striatum and reuptake in the nucleus accumbens (NAc), as measured by ex vivo fast scan cyclic voltammetry, was reduced for HFD-fed B6J females. Impairment in glucose metabolism explained HFD-induced changes in dopamine neurochemistry for B6J males and, to a lesser extent, Balb/c males. The relative expressions of protein markers associated with the activation of microglia, ionized calcium binding adaptor molecule (Iba1) and cluster of differentiation molecule 11b (CD11b) in the striatum were increased due to an HFD for B6J males but were unchanged or decreased amongst HFD-fed Balb/c mice. Conclusions: Our findings demonstrate that strain and sex influence the insulin- and microglia-dependent mechanisms of alterations to dopamine neurochemistry and associated behavior due to an HFD.

Altered structure and functional connection of subcortical gray matter in female patients with classical trigeminal neuralgia.

The etiology of classical trigeminal neuralgia (CTN) is still unclear. A better understanding of the cerebral structural and functional changes in female patients with CTN may provide important novel insights into the pathophysiologic mechanisms of female CTN. A total 37 female CTN patients were included and referred to MRI scans, comprising with 19 left CTN and 18 right CTN patients. We analyzed the volume and shape of subcortical gray matter (GM), and the functional connectivity (FC) between the accumbens nucleus (NAc) and whole brain in right and left CTN patients respectively. We found left CTN patients had a reduced right NAc volume compared to controls, similarly, the right CTN had the decreased volume in the left NAc. Vertex-wise shapes of right NAc in left CTN patients showed significant regional shape deformation on the anterior, medial and ventroposterior aspects, in contrast, left NAc of right CTN patients showed significant regional shape deformation on the anterior and posterior aspect. Furthermore, patients with left CTN showed significantly lower FC between the right NAc and right orbitofrontal cortex than control subjects. The volume of NAc in all CTN was significantly related to the perception of present pain intensity. The CTN might be majorly caused by volume reduction in NAc. A greater understanding of the neurobiological basis of pain-related changes in NAc will provide the knowledge for the development of novel NAc based therapeutic targets for pain management or even prevention in CTN patients.

Dopamine-mediated formation of a memory module in the nucleus accumbens for goal-directed navigation.

Spatial memories guide navigation efficiently toward desired destinations. However, the neuronal and circuit mechanisms underlying the encoding of goal locations and its translation into goal-directed navigation remain unclear. Here we demonstrate that mice rapidly form a spatial memory of a shelter during shelter experiences, guiding escape behavior toward the goal location-a shelter-when under threat. Dopaminergic neurons in the ventral tegmental area and their projection to the nucleus accumbens (NAc) encode safety signals associated with the shelter. Optogenetically induced phasic dopamine signals are sufficient to create a place memory that directs escape navigation. Converging dopaminergic and hippocampal glutamatergic inputs to the NAc mediate the formation of a goal-related memory within a subpopulation of NAc neurons during shelter experiences. Artificial co-activation of this goal-related NAc ensemble with neurons in the dorsal periaqueductal gray was sufficient to trigger memory-guided, rather than random, escape behavior. These findings provide causal evidence of cognitive circuit modules linking memory with goal-directed action.