Changes in dorsomedial striatum activity during expression of goal-directed vs. habit-like cue-induced cocaine seeking.

A preclinical model of cue exposure therapy, cue extinction, reduces cue-induced cocaine seeking that is goal-directed but not habit-like. Goal-directed and habitual behaviors differentially rely on the dorsomedial striatum (DMS) and dorsolateral striatum (DLS), but the effects of cue extinction on dorsal striatal responses to cue-induced drug seeking are unknown. We used fiber photometry in rats trained to self-administer cocaine paired with an audiovisual cue to examine how dorsal striatal intracellular calcium and extracellular dopamine activity differs between goal-directed and habit-like cue-induced cocaine seeking and how it is impacted by cue extinction. After minimal fixed-ratio training, rats showed enhanced DMS and DLS calcium responses to cue-reinforced compared to unreinforced lever presses. After rats were trained on goal-promoting fixed ratio schedules or habit-promoting second-order schedules of reinforcement, different patterns of dorsal striatal calcium and dopamine responses to cue-reinforced lever presses emerged. Rats trained on habit-promoting second-order schedules showed reduced DMS calcium responses and enhanced DLS dopamine responses to cue-reinforced lever presses. Cue extinction reduced calcium responses during subsequent drug seeking in the DMS, but not in the DLS. Therefore, cue extinction may reduce goal-directed behavior through its effects on the DMS, whereas habit-like behavior and the DLS are unaffected.

Keratan sulfate proteoglycan: putative template for neuroblast migratory and axonal fascicular pathways and fetal expression in globus pallidus, thalamus, and olfactory bulb.

Keratan sulfate (KS) is a proteoglycan secreted in the fetal brain astrocytes and radial glia into extracellular parenchyma as granulofilamentous deposits. KS surrounds neurons except dendritic spines, repelling glutamatergic and facilitating GABAergic axons. The same genes are expressed in both neuroblast migration and axonal growth. This study examines timing of KS during morphogenesis of some normally developing human fetal forebrain structures. Twenty normal human fetal brains from 9-41 weeks gestational age were studied at autopsy. KS was examined by immunoreactivity in formalin-fixed paraffin sections, plus other markers including synaptophysin, S-100ß protein, vimentin and nestin. Radial and tangential neuroblast migratory pathways from subventricular zone to cortical plate were marked by KS deposits as early as 9wk GA, shortly after neuroblast migration initiated. During later gestation this reactivity gradually diminished and disappeared by term. Long axonal fascicles of the internal capsule and short fascicles of intrinsic bundles of globus pallidus and corpus striatum also appeared as early as 9-12wk, as fascicular sleeves before axons even entered. Intense KS occurs in astrocytic cytoplasm and extracellular parenchyma at 9wk in globus pallidus, 15wk thalamus, 18wk corpus striatum, 22wk cortical plate, and hippocampus postnatally. Corpus callosum and anterior commissure do not exhibit KS at any age. Optic chiasm shows reactivity at the periphery but not around intrinsic subfasciculi. We postulate that KS forms a chemical template for many long and short axonal fascicles before axons enter and neuroblast migratory pathways at initiation of migration. Cross-immunoreactivity with aggrecan may render difficult molecular distinction.

Motor skill learning modulates striatal extracellular vesicles' content in a mouse model of Huntington's disease.

Huntington's disease (HD) is a neurological disorder caused by a CAG expansion in the Huntingtin gene (HTT). HD pathology mostly affects striatal medium-sized spiny neurons and results in an altered cortico-striatal function. Recent studies report that motor skill learning, and cortico-striatal stimulation attenuate the neuropathology in HD, resulting in an amelioration of some motor and cognitive functions. During physical training, extracellular vesicles (EVs) are released in many tissues, including the brain, as a potential means for inter-tissue communication. To investigate how motor skill learning, involving acute physical training, modulates EVs crosstalk between cells in the striatum, we trained wild-type (WT) and R6/1 mice, the latter with motor and cognitive deficits, on the accelerating rotarod test, and we isolated their striatal EVs. EVs from R6/1 mice presented alterations in the small exosome population when compared to WT. Proteomic analyses revealed that striatal R6/1 EVs recapitulated signaling and energy deficiencies present in HD. Motor skill learning in R6/1 mice restored the amount of EVs and their protein content in comparison to naïve R6/1 mice. Furthermore, motor skill learning modulated crucial pathways in metabolism and neurodegeneration. All these data provide new insights into the pathogenesis of HD and put striatal EVs in the spotlight to understand the signaling and metabolic alterations in neurodegenerative diseases. Moreover, our results suggest that motor learning is a crucial modulator of cell-to-cell communication in the striatum.

Microglia contribute to methamphetamine reinforcement and reflect persistent transcriptional and morphological adaptations to the drug.

Methamphetamine use disorder (MUD) is a chronic, relapsing disease that is characterized by repeated drug use despite negative consequences and for which there are currently no FDA-approved cessation therapeutics. Repeated methamphetamine (METH) use induces long-term gene expression changes in brain regions associated with reward processing and drug-seeking behavior, and recent evidence suggests that methamphetamine-induced neuroinflammation may also shape behavioral and molecular responses to the drug. Microglia, the resident immune cells in the brain, are principal drivers of neuroinflammatory responses and contribute to the pathophysiology of substance use disorders. Here, we investigated transcriptional and morphological changes in dorsal striatal microglia in response to methamphetamine-taking and during methamphetamine abstinence, as well as their functional contribution to drug-taking behavior. We show that methamphetamine self-administration induces transcriptional changes associated with protein folding, mRNA processing, immune signaling, and neurotransmission in dorsal striatal microglia. Importantly, many of these transcriptional changes persist through abstinence, a finding supported by morphological analyses. Functionally, we report that microglial ablation increases methamphetamine-taking, possibly involving neuroimmune and neurotransmitter regulation. In contrast, microglial depletion during abstinence does not alter methamphetamine-seeking. Taken together, these results suggest that methamphetamine induces both short and long-term changes in dorsal striatal microglia that contribute to altered drug-taking behavior and may provide valuable insights into the pathophysiology of MUD.

Expectation of pain and relief: A dynamical model of the neural basis for pain-trauma co-morbidity.

Posttraumatic Stress Disorder (PTSD) is highly co-morbid with chronic pain conditions. When present, PTSD significantly worsens chronic pain outcomes. Likewise, pain contributes to a more severe PTSD as evidenced by greater disability, more frequent use of harmful opioid analgesics and increased pain severity. The biomechanism behind this comorbidity is incompletely understood, however recent work strongly supports the widely-accepted role of expectation, in the entanglement of chronic pain and trauma symptoms. This work has shown that those with trauma have a maladaptive brain response while expecting stress and pain, whereas those with chronic pain may have a notable impairment in brain response while expecting pain relief. This dynamical expectation model of the interaction between neural systems underlying expectation of pain onset (traumatic stress) and pain offset (chronic pain) is biologically viable and may provide a biomechanistic insight into pain-trauma comorbidity. These predictive mechanisms work through interoceptive pathways in the brain critically the insula cortex. Here we highlight how the neural expectation-related mechanisms augment the existing models of pain and trauma to better understand the dynamics of pain and trauma comorbidity. These ideas will point to targeted complementary clinical approaches, based on mechanistically separable neural biophenotypes for the entanglement of chronic pain and trauma symptoms.

Short-term antipsychotic treatment reduces functional connectivity of the striatum in first-episode drug-naïve early-onset schizophrenia.

BACKGROUND: The striatum is thought to play a critical role in the pathophysiology and antipsychotic treatment of schizophrenia. Previous studies have revealed abnormal functional connectivity (FC) of the striatum in early-onset schizophrenia (EOS) patients. However, no prior studies have examined post-treatment changes of striatal FC in EOS patients. METHODS: We recruited 49 first-episode drug-naïve EOS patients to have resting-state functional magnetic resonance imaging scans at baseline and after 8 weeks of treatment with antipsychotics, along with baseline scanning of 34 healthy controls (HCs) for comparison purposes. We examined the FC values between each seed in striatal subregion and the rest of the brain. The Positive and Negative Syndrome Scale (PANSS) was applied to measure psychiatric symptoms in patients. RESULTS: Compared with HCs at baseline, EOS patients exhibited weaker FC of striatal subregions with several brain regions of the salience network and default mode network. Meanwhile, FC between the dorsal caudal putamen (DCP) and left supplementary motor area, as well as between the DCP and right postcentral gyrus, was negatively correlated with PANSS negative scores. Furthermore, after 8 weeks of treatment, EOS patients showed decreased FC between subregions of the putamen and the triangular part of inferior frontal gyrus, middle frontal gyrus, supramarginal gyrus and inferior parietal lobule. CONCLUSIONS: Decreased striatal FC is evident, even in the early stages of schizophrenia, and enhance our understanding of the neurodevelopmental abnormalities in schizophrenia. The findings also demonstrate that reduced striatal FC occurs after antipsychotic therapy, indicating that antipsychotic effects need to be accounted for when considering striatal FC abnormalities in schizophrenia.

In situ analysis of neuronal injury and neuroinflammation during HIV-1 infection.

BACKGROUND: Since the introduction of combination antiretroviral therapy (cART) the brain has become an important human immunodeficiency virus (HIV) reservoir due to the relatively low penetration of many drugs utilized in cART into the central nervous system (CNS). Given the inherent limitations of directly assessing acute HIV infection in the brains of people living with HIV (PLWH), animal models, such as humanized mouse models, offer the most effective means of studying the effects of different viral strains and their impact on HIV infection in the CNS. To evaluate CNS pathology during HIV-1 infection in the humanized bone marrow/liver/thymus (BLT) mouse model, a histological analysis was conducted on five CNS regions, including the frontal cortex, hippocampus, striatum, cerebellum, and spinal cord, to delineate the neuronal (MAP2ab, NeuN) and neuroinflammatory (GFAP, Iba-1) changes induced by two viral strains after 2 weeks and 8 weeks post-infection. RESULTS: Findings reveal HIV-infected human cells in the brain of HIV-infected BLT mice, demonstrating HIV neuroinvasion. Further, both viral strains, HIV-1JR-CSF and HIV-1CH040, induced neuronal injury and astrogliosis across all CNS regions following HIV infection at both time points, as demonstrated by decreases in MAP2ab and increases in GFAP fluorescence signal, respectively. Importantly, infection with HIV-1JR-CSF had more prominent effects on neuronal health in specific CNS regions compared to HIV-1CH040 infection, with decreasing number of NeuN+ neurons, specifically in the frontal cortex. On the other hand, infection with HIV-1CH040 demonstrated more prominent effects on neuroinflammation, assessed by an increase in GFAP signal and/or an increase in number of Iba-1+ microglia, across CNS regions. CONCLUSION: These findings demonstrate that CNS pathology is widespread during acute HIV infection. However, neuronal loss and the magnitude of neuroinflammation in the CNS is strain dependent indicating that strains of HIV cause differential CNS pathologies.

Low-dose radiation decreases Lrrk2 levels in the striatum of large mammalian brains: New venues to treat Parkinson's disease?

INTRODUCTION: Among gene mutations and variants linked to an increased risk of PD, mutations of leucine-rich repeat kinase 2 gene (LRRK2) are among the most frequently associated with early- and late-onset PD. Clinical and neuropathological characteristics of idiopathic-PD (iPD) and LRRK2-PD are similar, and these similarities suggest that the pathomechanisms between these two conditions are shared. LRRK2 mutations determine a gain-of-function and yield higher levels of lrrk2 across body tissues, including brain. On another side, recent animal studies supported the potential use of low dose radiation (LDR) to modify the pathomechanisms of diseases such as Alzheimer's disease (AD). METHODS: We assessed if a single total-body LDR (sLDR) exposure in normal swine could alter expression levels of the following PD-associated molecules: alpha-synuclein (α-syn), phosphorylated-α-synuclein (pα-syn), parkin, tyrosine hydroxylase (th), lrrk2, phosphorylated-lrrk2 (pS935-lrrk2), and some LRRK2 substrates (Rab8a, Rab12) across different brain regions. These proteins were measured in frontal cortex, hippocampus, striatum, thalamus/hypothalamus, and cerebellum of 9 radiated (RAD) vs. 6 sham (SH) swine after 28 days from a sLDR of 1.79Gy exposure. RESULTS: Western Blot analyses showed lowered lrrk2 levels in the striatum of RAD vs. SH swine (p < 0.05), with no differences across the remaining brain regions. None of the other protein levels differed between RAD and SH swine in any examined brain regions. No lrrk2 and p-lrrk2 (S935) levels differed in the lungs of RAD vs. SH swine. CONCLUSIONS: These findings show a specific striatal lrrk2 lowering effect due to LDR and support the potential use of LDR to interfere with the pathomechanisms of PD.

A cocaine-activated ensemble exerts increased control over behavior while decreasing in size.

BACKGROUND: Substance use disorder (SUD) is characterized by long-lasting changes in reward-related brain regions, such as the nucleus accumbens (NAc). Previous work has shown that cocaine exposure induces plasticity in broad, genetically-defined cell types in the NAc; however, in response to a stimulus, only a small percent of neurons are transcriptionally active - termed an ensemble. Here, we identify an Arc-expressing neuronal ensemble that has a unique trajectory of recruitment and causally controls drug self-administration after repeated, but not acute, cocaine exposure. METHOD: Using Arc-CreERT2 transgenic mice, we expressed transgenes in Arc+ ensembles activated by cocaine exposure [either acute (1 x 10mg/kg IP), or repeated (10 x 10mg/kg IP)]. Using genetic, optical, and physiological recording and manipulation strategies, we assessed the contribution of these ensembles to behaviors associated with SUD. RESULTS: Repeated cocaine exposure reduced the size of the ensemble, while simultaneously increasing its control over behavior. Neurons within the repeated cocaine ensemble were hyperexcitable and their optogenetic excitation was sufficient for reinforcement. Finally, lesioning the repeated cocaine, but not acute cocaine, ensemble blunted cocaine self-administration. Thus, repeated cocaine exposure reduced the size of the ensemble while simultaneously increasing its contributions to drug reinforcement. CONCLUSIONS: We show that repeated, but not acute, cocaine exposure induces a physiologically distinct ensemble characterized by the expression of the immediate early gene Arc, that is uniquely capable of modulating reinforcement behavior.

Pathological cell assembly dynamics in a striatal MSN network model.

Under normal conditions the principal cells of the striatum, medium spiny neurons (MSNs), show structured cell assembly activity patterns which alternate sequentially over exceedingly long timescales of many minutes. It is important to understand this activity since it is characteristically disrupted in multiple pathologies, such as Parkinson's disease and dyskinesia, and thought to be caused by alterations in the MSN to MSN lateral inhibitory connections and in the strength and distribution of cortical excitation to MSNs. To understand how these long timescales arise we extended a previous network model of MSN cells to include synapses with short-term plasticity, with parameters taken from a recent detailed striatal connectome study. We first confirmed the presence of sequentially switching cell clusters using the non-linear dimensionality reduction technique, Uniform Manifold Approximation and Projection (UMAP). We found that the network could generate non-stationary activity patterns varying extremely slowly on the order of minutes under biologically realistic conditions. Next we used Simulation Based Inference (SBI) to train a deep net to map features of the MSN network generated cell assembly activity to MSN network parameters. We used the trained SBI model to estimate MSN network parameters from ex-vivo brain slice calcium imaging data. We found that best fit network parameters were very close to their physiologically observed values. On the other hand network parameters estimated from Parkinsonian, decorticated and dyskinetic ex-vivo slice preparations were different. Our work may provide a pipeline for diagnosis of basal ganglia pathology from spiking data as well as for the design pharmacological treatments.

Volume electron microscopy for genetically and molecularly defined neural circuits.

The brain networks responsible for adaptive behavioral changes are based on the physical connections between neurons. Light and electron microscopy have long been used to study neural projections and the physical connections between neurons. Volume electron microscopy has recently expanded its scale of analysis due to methodological advances, resulting in complete wiring maps of neurites in a large volume of brain tissues and even entire nervous systems in a growing number of species. However, structural approaches frequently suffer from inherent limitations in which elements in images are identified solely by morphological criteria. Recently, an increasing number of tools and technologies have been developed to characterize cells and cellular components in the context of molecules and gene expression. These advancements include newly developed probes for visualization in electron microscopic images as well as correlative integration methods for the same elements across multiple microscopic modalities. Such approaches advance our understanding of interactions between specific neurons and circuits and may help to elucidate novel aspects of the basal ganglia network involving dopamine neurons. These advancements are expected to reveal mechanisms for processing adaptive changes in specific neural circuits that modulate brain functions.

Alterations of apparent diffusion coefficient from ultra high b-values in the bilateral thalamus and striatum in MRI-negative drug-resistant epilepsy.

OBJECTIVE: Subcortical nuclei such as the thalamus and striatum have been shown to be related to seizure modulation and termination, especially in drug-resistant epilepsy. Enhance diffusion-weighted imaging (eDWI) technique and tri-component model have been used in previous studies to calculate apparent diffusion coefficient from ultra high b-values (ADCuh). This study aimed to explore the alterations of ADCuh in the bilateral thalamus and striatum in MRI-negative drug-resistant epilepsy. METHODS: Twenty-nine patients with MRI-negative drug-resistant epilepsy and 18 healthy controls underwent eDWI scan with 15 b-values (0-5000 s/mm2). The eDWI parameters including standard ADC (ADCst), pure water diffusion (D), and ADCuh were calculated from the 15 b-values. Regions-of-interest (ROIs) analyses were conducted in the bilateral thalamus, caudate nucleus, putamen, and globus pallidus. ADCst, D, and ADCuh values were compared between the MRI-negative drug-resistant epilepsy patients and controls using multivariate generalized linear models. Inter-rater reliability was assessed using the intra-class correlation coefficient (ICC) and Bland-Altman (BA) analysis. False discovery rate (FDR) method was applied for multiple comparisons correction. RESULTS: ADCuh values in the bilateral thalamus, caudate nucleus, putamen, and globus pallidus in MRI-negative drug-resistant epilepsy were significantly higher than those in the healthy control subjects (all p < 0.05, FDR corrected). SIGNIFICANCE: The alterations of the ADCuh values in the bilateral thalamus and striatum in MRI-negative drug-resistant epilepsy might reflect abnormal membrane water permeability in MRI-negative drug-resistant epilepsy. ADCuh might be a sensitive measurement for evaluating subcortical nuclei-related brain damage in epilepsy patients. PLAIN LANGUAGE SUMMARY: This study aimed to explore the alterations of apparent diffusion coefficient calculated from ultra high b-values (ADCuh) in the subcortical nuclei such as the bilateral thalamus and striatum in MRI-negative drug-resistant epilepsy. The bilateral thalamus and striatum showed higher ADCuh in epilepsy patients than healthy controls. These findings may add new evidences of subcortical nuclei abnormalities related to water and ion hemostasis in epilepsy patients, which might help to elucidate the underlying epileptic neuropathophysiological mechanisms and facilitate the exploration of therapeutic targets.

5-HT4R agonism reduces L-DOPA-induced dyskinesia via striatopallidal neurons in unilaterally 6-OHDA lesioned mice.

Parkinson's disease is caused by a selective vulnerability and cell loss of dopaminergic neurons of the Substantia Nigra pars compacta and, consequently, striatal dopamine depletion. In Parkinson's disease therapy, dopamine loss is counteracted by the administration of L-DOPA, which is initially effective in ameliorating motor symptoms, but over time leads to a burdening side effect of uncontrollable jerky movements, termed L-DOPA-induced dyskinesia. To date, no efficient treatment for dyskinesia exists. The dopaminergic and serotonergic systems are intrinsically linked, and in recent years, a role has been established for pre-synaptic 5-HT1a/b receptors in L-DOPA-induced dyskinesia. We hypothesized that post-synaptic serotonin receptors may have a role and investigated the effect of modulation of 5-HT4 receptor on motor symptoms and L-DOPA-induced dyskinesia in the unilateral 6-OHDA mouse model of Parkinson's disease. Administration of RS 67333, a 5-HT4 receptor partial agonist, reduces L-DOPA-induced dyskinesia without altering L-DOPA's pro-kinetic effect. In the dorsolateral striatum, we find 5-HT4 receptor to be predominantly expressed in D2R-containing medium spiny neurons, and its expression is altered by dopamine depletion and L-DOPA treatment. We further show that 5-HT4 receptor agonism not only reduces L-DOPA-induced dyskinesia, but also enhances the activation of the cAMP-PKA pathway in striatopallidal medium spiny neurons. Taken together, our findings suggest that agonism of the post-synaptic serotonin receptor 5-HT4 may be a novel therapeutic approach to reduce L-DOPA-induced dyskinesia.

Representation of rhythmic chunking in striatum of mice executing complex continuous movement sequences.

We used a step-wheel system to examine the activity of striatal projection neurons as mice practiced stepping on complexly arranged foothold pegs in this Ferris-wheel-like device to receive reward. Sets of dorsolateral striatal projection neurons were sensitive to specific parameters of repetitive motor coordination during the runs. They responded to combinations of the parameters of continuous movements (interval, phase, and repetition), forming "chunking responses"-some for combinations of these parameters across multiple body parts. Recordings in sensorimotor cortical areas exhibited notably fewer such responses but were documented for smaller neuron sets whose heterogeneity was significant. Striatal movement encoding via chunking responsivity could provide insight into neural strategies governing effective motor control by the striatum. It is possible that the striking need for external rhythmic cuing to allow movement sequences by Parkinson's patients could, at least in part, reflect dysfunction in such striatal coding.

Brain alterations in individuals with exercise dependence: A multimodal neuroimaging investigation.

Background: Exercise dependence (ED) is characterised by behavioural and psychological symptoms that resemble those of substance use disorders. However, it remains inconclusive whether ED is accompanied by similar brain alterations as seen in substance use disorders. Therefore, we investigated brain alterations in individuals with ED and inactive control participants. Methods: In this cross-sectional neuroimaging investigation, 29 individuals with ED as assessed with the Exercise Dependence Scale (EDS) and 28 inactive control participants (max one hour exercising per week) underwent structural and functional resting-state magnetic resonance imaging (MRI). Group differences were explored using voxel-based morphometry and functional connectivity analyses. Analyses were restricted to the striatum, amygdala, and inferior frontal gyrus (IFG). Exploratory analyses tested whether relationships between brain structure and function were differently related to EDS subscales among groups. Results: No structural differences were found between the two groups. However, right IFG and bilateral putamen volumes were differently related to the EDS subscales "time" and "tolerance", respectively, between the two groups. Resting-state functional connectivity was increased from right IFG to right superior parietal lobule in individuals with ED compared to inactive control participants. Furthermore, functional connectivity of the angular gyrus to the left IFG and bilateral caudate showed divergent relationships to the EDS subscale "tolerance" among groups. Discussion: The findings suggest that ED may be accompanied by alterations in cognition-related brain structures, but also functional changes that may drive compulsive habitual behaviour. Further prospective studies are needed to disentangle beneficial and detrimental brain effects of ED.

Dopamine-mediated plasticity preserves excitatory connections to direct pathway striatal projection neurons and motor function in a mouse model of Parkinson's disease.

The cardinal symptoms of Parkinson's disease (PD) such as bradykinesia and akinesia are debilitating, and treatment options remain inadequate. The loss of nigrostriatal dopamine neurons in PD produces motor symptoms by shifting the balance of striatal output from the direct (go) to indirect (no-go) pathway in large part through changes in the excitatory connections and intrinsic excitabilities of the striatal projection neurons (SPNs). Here, we report using two different experimental models that a transient increase in striatal dopamine and enhanced D1 receptor activation, during 6-OHDA dopamine depletion, prevent the loss of mature spines and dendritic arbors on direct pathway projection neurons (dSPNs) and normal motor behavior for up to 5 months. The primary motor cortex and midline thalamic nuclei provide the major excitatory connections to SPNs. Using ChR2-assisted circuit mapping to measure inputs from motor cortex M1 to dorsolateral dSPNs, we observed a dramatic reduction in both experimental model mice and controls following dopamine depletion. Changes in the intrinsic excitabilities of SPNs were also similar to controls following dopamine depletion. Future work will examine thalamic connections to dSPNs. The findings reported here reveal previously unappreciated plasticity mechanisms within the basal ganglia that can be leveraged to treat the motor symptoms of PD.

Comprehensive glycomic and proteomic analysis of mouse striatum and lateral hypothalamus following repeated exposures to cocaine or methamphetamine.

Substance use disorder is a major concern, with few therapeutic options. Heparan sulfate (HS) and chondroitin sulfate (CS) interact with a plethora of growth factors and their receptors and have profound effects on cellular signaling. Thus, targeting these dynamic interactions might represent a potential novel therapeutic modality. In the present study, we performed mass spectrometry-based glycomic and proteomic analysis to understand the effects of cocaine and methamphetamine (METH) on HS, CS, and the proteome of two brain regions critically involved in drug addiction: the lateral hypothalamus (LH) and the striatum (ST). We observed that cocaine and METH significantly alter HS and CS abundances as well as sulfate contents and composition. In particular, repeated METH or cocaine treatments reduced CS 4-O-sulfation and increased CS 6-O-sulfation. Since C4S and C6S exercise differential effects on axon growth, regeneration and plasticity, these changes likely contribute to drug-induced neural plasticity in these brain regions. Notably, we observed that restoring these alterations by increasing CS 4-0 levels in the LH by adeno-associated virus (AAV) delivery of an shRNA to Arylsulfatase B (N-acetylgalactosamine-4-sulfatase, ARSB) ameliorated anxiety and prevented the expression of preference for cocaine in a novelty induced conditioned place preference test during cocaine withdrawal. Finally, proteomics analyses revealed a number of aberrant proteins in METH- and cocaine-treated vs. saline-treated mice, including MYPR, KCC2A, SYN2, TENR, CALX, ANXA7, HDGF, NCAN, and CSPG5, and oxidative phosphorylation among the top perturbed pathway. Taken together, these data support the role of HS, CS, and associated proteins in stimulants abuse and suggest that manipulation of HSPGs can represent a novel therapeutic strategy.

Sexual dimorphism in histamine regulation of striatal dopamine.

Background: Many neuropsychiatric disorders show sex differences in prevalence and presentation. For example, Tourette's Syndrome (TS) is diagnosed 3-5 times more often in males. Dopamine modulation of the basal ganglia is implicated in numerous neuropsychiatric conditions, including TS. Motivated by an unexpected genetic finding in a family with TS, we previously characterized the modulation of striatal dopamine by histamine. Methods: We used microdialysis to analyze striatal dopamine response to the targeted infusion of histamine and histamine agonists. siRNA knockdown of histamine receptors was used to identify the cellular mediators of observed effects. Results: Intracerebroventricular histamine reduced striatal dopamine in male mice, replicating previous work. Unexpectedly, histamine increased striatal dopamine in females. Targeted infusion of selected agonists revealed that the effect in males depends on H2R receptors in the substantia nigra pars compacta (SNc). Knockdown of H2R in SNc GABAergic neurons abrogated the effect, identifying these cells as a key locus of histamine's regulation of dopamine in males. In females, in contrast, H2R had no role; instead, H3R agonists in the striatum increased striatal dopamine. Strikingly, the effect of histamine on dopamine in females was modulated by the estrous cycle, appearing in estrus/proestrus but not in metestrus/diestrus. Conclusions: These findings confirm the regulation of striatal dopamine by histamine but identify marked sexual dimorphism in and estrous modulation of this effect. These findings may shed light on the mechanistic underpinnings of other sex differences in the striatal circuitry, perhaps including the marked sex differences seen in TS and related neuropsychiatric conditions.

Neuroprotective effect of marrubiin against MPTP-induced experimental Parkinson's disease in male wistar rats.

In this work, we have analyzed the neuroprotective activity of marrubiin against MPTP-induced Parkinson's disease (PD) in rat brains. MPTP (1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine) a neurotoxin was administered intraperitoneally (i.p.,) to rats and then treated using marrubiin. After marrubiin treatment, rats were trained, and tested for behavioral analyses like cognitive performance, open field test, rotarod test, grip strength test, beam walking test, the status of body weight, and striatal levels of neurotransmitters like dopamine, norepinephrine, serotonin, DOPAC, homovanillic acid, 5-hydroxy indole acetic acid, the status of oxidative stress markers like LPO, protein carbonyl content (PCC), Xanthine oxidase (XO), and status of antioxidant enzyme levels like SOD, CAT, GPX in the striatum and hippocampal tissues, status of neuroinflammatory markers like TNF-α, IL1ß, IL-6, and status of histological architecture in brain striatum were also analyzed. All these parameters were significantly (p < 0.05) abnormal in MPTP-induced rats. Marrubiin (MB) treated shows significant (p < 0.05) near normal behavioral restoration in cognitive performance, open field, rotarod, grip strength, and beam walking tests. Furthermore, the status of body weight, and levels of neurotransmitters, were also significantly (p < 0.05) reversed to near normalcy in marrubiin-treated rats. Similarly, oxidative stress, antioxidant enzyme levels in the striatum and hippocampal tissues, TNF-α, IL1ß, IL-6 levels, and histological architecture were noted to be restored to near normalcy in marrubiin-treated rats. Collectively, our preliminary results highlight the neuroprotective ability of marrubiin. However, the cellular and biochemical mechanisms of marrubiin's neuroprotective ability have to be studied in detail.

Behavioral dishonesty in multiscenes: Associations with trait honesty and neural patterns during (dis)honesty video-watching.

Cross-situational inconsistency is common in the expression of honesty traits; yet, there is insufficient emphasis on behavioral dishonesty across multiple contexts. The current study aimed to investigate behavioral dishonesty in various contexts and reveal the associations between trait honesty, behavioral dishonesty, and neural patterns of observing others behave honestly or dishonestly in videos (abbr.: (dis)honesty video-watching). First, the results revealed limitations in using trait honesty to reflect variations in dishonest behaviors and predict behavioral dishonesty. The finding highlights the importance of considering neural patterns in understanding and predicting dishonest behaviors. Second, by comparing the predictive performance of seven types of data across three neural networks, the results showed that functional connectivity in the hypothesis-driven network during (dis)honesty video-watching provided the highest predictive power in predicting multitask behavioral dishonesty. Last, by applying the feature elimination method, the midline self-referential regions (medial prefrontal cortex, posterior cingulate cortex, and anterior cingulate cortex), anterior insula, and striatum were identified as the most informative brain regions in predicting behavioral dishonesty. In summary, the study offered insights into individual differences in deception and the intricate connections among trait honesty, behavioral dishonesty, and neural patterns during (dis)honesty video-watching.