Activation of CGRP neurons in the parabrachial nucleus suppresses addictive behavior.

Punishment such as electric shock or physical discipline employs a mixture of physical pain and emotional distress to induce behavior modification. However, a neural circuit that produces behavior modification by selectively focusing the emotional component, while bypassing the pain typically induced by peripheral nociceptor activation, is not well studied. Here, we show that genetically silencing the activity of neurons expressing calcitonin gene-related peptide (CGRP) in the parabrachial nucleus blocks the suppression of addictive-like behavior induced by footshock. Furthermore, activating CGRP neurons suppresses not only addictive behavior induced by self-stimulating dopamine neurons but also behavior resulting from self-administering cocaine, without eliciting nocifensive reactions. Moreover, among multiple downstream targets of CGRP neurons, terminal activation of CGRP in the central amygdala is effective, mimicking the results of cell body stimulation. Our results indicate that unlike conventional electric footshock, stimulation of CGRP neurons does not activate peripheral nociceptors but effectively curb addictive behavior.

Tyrosine Hydroxylase Inhibitors and Dopamine Receptor Agonists Combination Therapy for Parkinson's Disease.

There are currently no disease-modifying therapies for Parkinson's disease (PD), a progressive neurodegenerative disorder associated with dopaminergic neuronal loss. There is increasing evidence that endogenous dopamine (DA) can be a pathological factor in neurodegeneration in PD. Tyrosine hydroxylase (TH) is the key rate-limiting enzyme for DA generation. Drugs that inhibit TH, such as alpha-methyltyrosine (α-MT), have recently been shown to protect against neurodegeneration in various PD models. DA receptor agonists can activate post-synaptic DA receptors to alleviate DA-deficiency-induced PD symptoms. However, DA receptor agonists have no therapeutic effects against neurodegeneration. Thus, a combination therapy with DA receptor agonists plus TH inhibitors may be an attractive therapeutic approach. TH inhibitors can protect and promote the survival of remaining dopaminergic neurons in PD patients' brains, whereas DA receptor agonists activate post-synaptic DA receptors to alleviate PD symptoms. Additionally, other PD drugs, such as N-acetylcysteine (NAC) and anticholinergic drugs, may be used as adjunctive medications to improve therapeutic effects. This multi-drug cocktail may represent a novel strategy to protect against progressive dopaminergic neurodegeneration and alleviate PD disease progression.

BDNF/TrkB activators in Parkinson's disease: A new therapeutic strategy.

Parkinson's disease (PD) is a neurodegenerative disorder of the brain and is manifested by motor and non-motor symptoms because of degenerative changes in dopaminergic neurons of the substantia nigra. PD neuropathology is associated with mitochondrial dysfunction, oxidative damage and apoptosis. Thus, the modulation of mitochondrial dysfunction, oxidative damage and apoptosis by growth factors could be a novel boulevard in the management of PD. Brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin receptor kinase type B (TrkB) are chiefly involved in PD neuropathology. BDNF promotes the survival of dopaminergic neurons in the substantia nigra and enhances the functional activity of striatal neurons. Deficiency of the TrkB receptor triggers degeneration of dopaminergic neurons and accumulation of α-Syn in the substantia nigra. As well, BDNF/TrkB signalling is reduced in the early phase of PD neuropathology. Targeting of BDNF/TrkB signalling by specific activators may attenuate PD neuropathology. Thus, this review aimed to discuss the potential role of BDNF/TrkB activators against PD. In conclusion, BDNF/TrkB signalling is decreased in PD and linked with disease severity and long-term complications. Activation of BDNF/TrkB by specific activators may attenuate PD neuropathology.

Transcriptional signatures of fentanyl use in the mouse ventral tegmental area.

Synthetic opioids such as fentanyl contribute to the vast majority of opioid-related overdose deaths, but fentanyl use remains broadly understudied. Like other substances with misuse potential, opioids cause lasting molecular adaptations to brain reward circuits, including neurons in the ventral tegmental area (VTA). The VTA contains numerous cell types that play diverse roles in opioid use and relapse; however, it is unknown how fentanyl experience alters the transcriptional landscape in specific subtypes. Here, we performed single nuclei RNA sequencing to study transcriptional programs in fentanyl-experienced mice. Male and female C57/BL6 mice self-administered intravenous fentanyl (1.5 µg/kg/infusion) or saline for 10 days. After 24 h abstinence, VTA nuclei were isolated and prepared for sequencing on the 10× platform. We identified different patterns of gene expression across cell types. In dopamine neurons, we found enrichment of genes involved in growth hormone signalling. In dopamine-glutamate-GABA combinatorial neurons, and some GABA neurons, we found enrichment of genes involved in Pi3k-Akt signalling. In glutamate neurons, we found enrichment of genes involved in cholinergic signalling. We identified transcriptional regulators for the differentially expressed genes in each neuron cluster, including downregulated transcriptional repressor Bcl6, and upregulated transcription factor Tcf4. We also compared the fentanyl-induced gene expression changes identified in mouse VTA with a published rat dataset in bulk VTA, and found overlap in genes related to GABAergic signalling and extracellular matrix interaction. Together, we provide a comprehensive picture of how fentanyl self-administration alters the transcriptional landscape of the mouse VTA that serves as the foundation for future mechanistic studies.

A dopamine mechanism for reward maximization.

Individual survival and evolutionary selection require biological organisms to maximize reward. Economic choice theories define the necessary and sufficient conditions, and neuronal signals of decision variables provide mechanistic explanations. Reinforcement learning (RL) formalisms use predictions, actions, and policies to maximize reward. Midbrain dopamine neurons code reward prediction errors (RPE) of subjective reward value suitable for RL. Electrical and optogenetic self-stimulation experiments demonstrate that monkeys and rodents repeat behaviors that result in dopamine excitation. Dopamine excitations reflect positive RPEs that increase reward predictions via RL; against increasing predictions, obtaining similar dopamine RPE signals again requires better rewards than before. The positive RPEs drive predictions higher again and thus advance a recursive reward-RPE-prediction iteration toward better and better rewards. Agents also avoid dopamine inhibitions that lower reward prediction via RL, which allows smaller rewards than before to elicit positive dopamine RPE signals and resume the iteration toward better rewards. In this way, dopamine RPE signals serve a causal mechanism that attracts agents via RL to the best rewards. The mechanism improves daily life and benefits evolutionary selection but may also induce restlessness and greed.

Multi-omics integration of scRNA-seq time series data predicts new intervention points for Parkinson's disease.

Parkinson's disease (PD) is a complex neurodegenerative disorder without a cure. The onset of PD symptoms corresponds to 50% loss of midbrain dopaminergic (mDA) neurons, limiting early-stage understanding of PD. To shed light on early PD development, we study time series scRNA-seq datasets of mDA neurons obtained from patient-derived induced pluripotent stem cell differentiation. We develop a new data integration method based on Non-negative Matrix Tri-Factorization that integrates these datasets with molecular interaction networks, producing condition-specific "gene embeddings". By mining these embeddings, we predict 193 PD-related genes that are largely supported (49.7%) in the literature and are specific to the investigated PINK1 mutation. Enrichment analysis in Kyoto Encyclopedia of Genes and Genomes pathways highlights 10 PD-related molecular mechanisms perturbed during early PD development. Finally, investigating the top 20 prioritized genes reveals 12 previously unrecognized genes associated with PD that represent interesting drug targets.

Gut microbiota produces biofilm-associated amyloids with potential for neurodegeneration.

Age-related neurodegenerative diseases involving amyloid aggregation remain one of the biggest challenges of modern medicine. Alterations in the gastrointestinal microbiome play an active role in the aetiology of neurological disorders. Here, we dissect the amyloidogenic properties of biofilm-associated proteins (BAPs) of the gut microbiota and their implications for synucleinopathies. We demonstrate that BAPs are naturally assembled as amyloid-like fibrils in insoluble fractions isolated from the human gut microbiota. We show that BAP genes are part of the accessory genomes, revealing microbiome variability. Remarkably, the abundance of certain BAP genes in the gut microbiome is correlated with Parkinson's disease (PD) incidence. Using cultured dopaminergic neurons and Caenorhabditis elegans models, we report that BAP-derived amyloids induce α-synuclein aggregation. Our results show that the chaperone-mediated autophagy is compromised by BAP amyloids. Indeed, inoculation of BAP fibrils into the brains of wild-type mice promote key pathological features of PD. Therefore, our findings establish the use of BAP amyloids as potential targets and biomarkers of α-synucleinopathies.

Orexin B protects dopaminergic neurons from 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity associated with reduced extracellular signal-regulated kinase phosphorylation.

BACKGROUND: The loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) is a major pathological hallmark of Parkinson's disease (PD). Orexin B (OXB) has been reported to promote the growth of DA neurons. However, the roles of OXB in the degeneration of DA neurons still remained not fully clear. METHODS: An in vivo PD model was constructed by administrating 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice. Pole test was performed to investigate the motor function of mice and the number of DA neurons was detected by immunofluorescence (IF). A PD cell model was established by treating SH-SY5Y cells with 1-methyl-4-phenylpyridinium (MPP+). OXB was added to the culture medium 2 h after MPP + treatment. Microscopic analysis was carried out to investigate the function of OXB in the cell model of PD 24 h after MPP + challenge. RNA-Seq analysis of the PD cell model was performed to explore the possible mechanisms. Western blot was used to detect the phosphorylation levels of extracellular signal-regulated kinase (ERK). RESULTS: OXB significantly decreased the DA neurons death caused by MPTP, alleviated MPP+-induced neurotoxicity in SH-SY5Y cells, and robustly enhanced the weight and motor ability of PD mice. Besides, RNA-Seq analysis demonstrated that the mitogen-activated protein kinase (MAPK) pathway was involved in the pathology of PD. Furthermore, MPP + led to increased levels of phosphorylation of ERK (p-ERK), OXB treatment significantly decreased the levels of p-ERK in MPP+-treated SH-SY5Y cells. CONCLUSIONS: This study demonstrated that OXB exerts a neuroprotective role associated with reduced ERK phosphorylation in the PD model. This suggests that OXB may have therapeutic potential for treatment of PD.

LRRK2 kinase inhibition protects against Parkinson's disease-associated environmental toxicants.

Idiopathic Parkinson's disease (PD) is epidemiologically linked with exposure to toxicants such as pesticides and solvents, which comprise a wide array of chemicals that pollute our environment. While most are structurally distinct, a common cellular target for their toxicity is mitochondrial dysfunction, a key pathological trigger involved in the selective vulnerability of dopaminergic neurons. We and others have shown that environmental mitochondrial toxicants such as the pesticides rotenone and paraquat, and the organic solvent trichloroethylene (TCE) appear to be influenced by the protein LRRK2, a genetic risk factor for PD. As LRRK2 mediates vesicular trafficking and influences endolysosomal function, we postulated that LRRK2 kinase activity may inhibit the autophagic removal of toxicant damaged mitochondria, resulting in elevated oxidative stress. Conversely, we suspected that inhibition of LRRK2, which has been shown to be protective against dopaminergic neurodegeneration caused by mitochondrial toxicants, would reduce the intracellular production of reactive oxygen species (ROS) and prevent mitochondrial toxicity from inducing cell death. To do this, we tested in vitro if genetic or pharmacologic inhibition of LRRK2 (MLi2) protected against ROS caused by four toxicants associated with PD risk - rotenone, paraquat, TCE, and tetrachloroethylene (PERC). In parallel, we assessed if LRRK2 inhibition with MLi2 could protect against TCE-induced toxicity in vivo, in a follow up study from our observation that TCE elevated LRRK2 kinase activity in the nigrostriatal tract of rats prior to dopaminergic neurodegeneration. We found that LRRK2 inhibition blocked toxicant-induced ROS and promoted mitophagy in vitro, and protected against dopaminergic neurodegeneration, neuroinflammation, and mitochondrial damage caused by TCE in vivo. We also found that cells with the LRRK2 G2019S mutation displayed exacerbated levels of toxicant induced ROS, but this was ameliorated by LRRK2 inhibition with MLi2. Collectively, these data support a role for LRRK2 in toxicant-induced mitochondrial dysfunction linked to PD risk through oxidative stress and the autophagic removal of damaged mitochondria.

Mesostriatal dopamine is sensitive to changes in specific cue-reward contingencies.

Learning causal relationships relies on understanding how often one event precedes another. To investigate how dopamine neuron activity and neurotransmitter release change when a retrospective relationship is degraded for a specific pair of events, we used outcome-selective Pavlovian contingency degradation in rats. Conditioned responding was attenuated for the cue-reward contingency that was degraded, as was dopamine neuron activity in the midbrain and dopamine release in the ventral striatum in response to the cue and subsequent reward. Contingency degradation also abolished the trial-by-trial history dependence of the dopamine responses at the time of trial outcome. This profile of changes in cue- and reward-evoked responding is not easily explained by a standard reinforcement learning model. An alternative model based on learning causal relationships was better able to capture dopamine responses during contingency degradation, as well as conditioned behavior following optogenetic manipulations of dopamine during noncontingent rewards. Our results suggest that mesostriatal dopamine encodes the contingencies between meaningful events during learning.

Dopamine-sensitive neurons in the mesencephalic locomotor region control locomotion initiation, stop, and turns.

The locomotor role of dopaminergic neurons is traditionally attributed to their ascending projections to the basal ganglia, which project to the mesencephalic locomotor region (MLR). In addition, descending dopaminergic projections to the MLR are present from basal vertebrates to mammals. However, the neurons targeted in the MLR and their behavioral role are unknown in mammals. Here, we identify genetically defined MLR cells that express D1 or D2 receptors and control different motor behaviors in mice. In the cuneiform nucleus, D1-expressing neurons promote locomotion, while D2-expressing neurons stop locomotion. In the pedunculopontine nucleus, D1-expressing neurons promote locomotion, while D2-expressing neurons evoke ipsilateral turns. Using RNAscope, we show that MLR dopamine-sensitive neurons comprise a combination of glutamatergic, GABAergic, and cholinergic neurons, suggesting that different neurotransmitter-based cell types work together to control distinct behavioral modules. Altogether, our study uncovers behaviorally relevant cell types in the mammalian MLR based on the expression of dopaminergic receptors.

Non-HLA angiotensin-type-1 receptor autoantibodies mediate the long-term loss of grafted neurons in Parkinson's disease models.

BACKGROUND: Clinical trials have provided evidence that transplants of dopaminergic precursors, which may be replaced by new in vitro stem cell sources, can integrate into the host tissue, and alleviate motor symptoms in Parkinson´s disease (PD). In some patients, deterioration of graft function occurred several months after observing a graft-derived functional improvement. Rejection of peripheral organs was initially related to HLA-specific antibodies. However, the role of non-HLA antibodies is now considered also relevant for rejection. Angiotensin-II type-1 receptor autoantibodies (AT1-AA) act as agonists of the AT1 receptors. AT1-AA are the non-HLA antibodies most widely associated with graft dysfunction or rejection after transplantation of different solid organs and hematopoietic stem cells. However, it is not known about the presence and possible functional effects of AT1-AA in dopaminergic grafts, and the effects of treatment with AT1 receptor blockers (ARBs) such as candesartan on graft survival. METHODS: In a 6-hydroxydopamine PD rat model, we studied the short-term (10 days)- and long-term (3 months) effects of chronic treatment with the ARB candesartan on survival of grafted dopaminergic neurons and microglial graft infiltration, as well as the effects of dopaminergic denervation and grafting on serum and CSF AT1-AA levels. The expression of AT1 receptors in grafted neurons was determined by laser capture microdissection. RESULTS: At the early period post-grafting, the number of grafted dopaminergic neurons that survived was not significantly different between treated and untreated hosts (i.e., control rats and rats treated with candesartan), probably because, just after grafting, other deleterious factors are predominant for dopaminergic cell death, such as mechanical trauma, lack of growth factors/nutrients and ischemia. However, several months post-grafting, we observed a significantly higher number of surviving dopaminergic neurons and a higher density of striatal dopaminergic terminals in the candesartan-treated group. For several months, grafted rats showed blood and cerebrospinal fluid levels of AT1-AA higher than normal controls, and also higher AT1-AA levels than non-grafted parkinsonian rats. CONCLUSIONS: The results suggest the use of ARBs such as candesartan in PD patients, particularly before and after dopaminergic grafts, and the need to monitor AT1-AA levels in PD patients, particularly in those candidates for dopaminergic grafting.

Adenosine A2A Receptor Blockade Provides More Effective Benefits at the Onset Rather than after Overt Neurodegeneration in a Rat Model of Parkinson's Disease.

Adenosine A2A receptor (A2AR) antagonists are the leading nondopaminergic therapy to manage Parkinson's disease (PD) since they afford both motor benefits and neuroprotection. PD begins with a synaptic dysfunction and damage in the striatum evolving to an overt neuronal damage of dopaminergic neurons in the substantia nigra. We tested if A2AR antagonists are equally effective in controlling these two degenerative processes. We used a slow intracerebroventricular infusion of the toxin MPP+ in male rats for 15 days, which caused an initial loss of synaptic markers in the striatum within 10 days, followed by a neuronal loss in the substantia nigra within 30 days. Interestingly, the initial loss of striatal nerve terminals involved a loss of both dopaminergic and glutamatergic synaptic markers, while GABAergic markers were preserved. The daily administration of the A2AR antagonist SCH58261 (0.1 mg/kg, i.p.) in the first 10 days after MPP+ infusion markedly attenuated both the initial loss of striatal synaptic markers and the subsequent loss of nigra dopaminergic neurons. Strikingly, the administration of SCH58261 (0.1 mg/kg, i.p. for 10 days) starting 20 days after MPP+ infusion was less efficacious to attenuate the loss of nigra dopaminergic neurons. This prominent A2AR-mediated control of synaptotoxicity was directly confirmed by showing that the MPTP-induced dysfunction (MTT assay) and damage (lactate dehydrogenase release assay) of striatal synaptosomes were prevented by 50 nM SCH58261. This suggests that A2AR antagonists may be more effective to counteract the onset rather than the evolution of PD pathology.

Reorganization of dopamine circuitry in the anterior corpus callosum between early adolescence and adulthood in the mouse.

The maturation of forebrain dopamine circuitry occurs over multiple developmental periods, extending from early postnatal life until adulthood, with the precise timing of maturation defined by the target region. We recently demonstrated in the adult mouse brain that axon terminals arising from midbrain dopamine neurons innervate the anterior corpus callosum and that oligodendrocyte lineage cells in this white matter tract express dopamine receptor transcripts. Whether corpus callosal dopamine circuitry undergoes maturational changes between early adolescence and adulthood is unknown but may be relevant to understanding the dramatic micro- and macro-anatomical changes that occur in the corpus callosum of multiple species during early adolescence, including in the degree of myelination. Using quantitative neuroanatomy, we show that dopamine innervation in the forceps minor, but not the rostral genu, of the corpus callosum, is greater during early adolescence (P21) compared to adulthood (>P90) in wild-type mice. We further demonstrate with RNAscope that, as in the adult, Drd1 and Drd2 transcripts are expressed at higher levels in oligodendrocyte precursor cells (OPCs) and decline as these cells differentiate into oligodendrocytes. In addition, the number of OPCs that express Drd1 transcripts during early adolescence is double the number of those expressing the transcript during early adulthood. These data further implicate dopamine in axon myelination and myelin regulation. Moreover, because developmental (activity-independent) myelination peaks during early adolescence, with experience-dependent (activity-dependent) myelination greatest during early adulthood, our data suggest that potential roles of dopamine on callosal myelination shift between early adolescence and adulthood, from a developmental role to an experience-dependent role.

Aplp1 interacts with Lag3 to facilitate transmission of pathologic α-synuclein.

Pathologic α-synuclein (α-syn) spreads from cell-to-cell, in part, through binding to the lymphocyte-activation gene 3 (Lag3). Here we report that amyloid ß precursor-like protein 1 (Aplp1) interacts with Lag3 that facilitates the binding, internalization, transmission, and toxicity of pathologic α-syn. Deletion of both Aplp1 and Lag3 eliminates the loss of dopaminergic neurons and the accompanying behavioral deficits induced by α-syn preformed fibrils (PFF). Anti-Lag3 prevents the internalization of α-syn PFF by disrupting the interaction of Aplp1 and Lag3, and blocks the neurodegeneration induced by α-syn PFF in vivo. The identification of Aplp1 and the interplay with Lag3 for α-syn PFF induced pathology deepens our insight about molecular mechanisms of cell-to-cell transmission of pathologic α-syn and provides additional targets for therapeutic strategies aimed at preventing neurodegeneration in Parkinson's disease and related α-synucleinopathies.

Ventral pallidum GABA and glutamate neurons drive approach and avoidance through distinct modulation of VTA cell types.

The ventral pallidum (VP) contains GABA and glutamate neurons projecting to ventral tegmental area (VTA) whose stimulation drives approach and avoidance, respectively. Yet little is known about the mechanisms by which VP cell types shape VTA activity and drive behavior. Here, we found that both VP GABA and glutamate neurons were activated during approach to reward or by delivery of an aversive stimulus. Stimulation of VP GABA neurons inhibited VTA GABA, but activated dopamine and glutamate neurons. Remarkably, stimulation-evoked activation was behavior-contingent such that VTA recruitment was inhibited when evoked by the subject's own action. Conversely, VP glutamate neurons activated VTA GABA, as well as dopamine and glutamate neurons, despite driving aversion. However, VP glutamate neurons evoked dopamine in aversion-associated ventromedial nucleus accumbens (NAc), but reduced dopamine release in reward-associated dorsomedial NAc. These findings show how heterogeneous VP projections to VTA can be engaged to shape approach and avoidance behaviors.

Dihydroquercetin alleviates dopamine neuron loss via regulating TREM2 activation.

BACKGROUND: Parkinson's disease (PD) is a prevalent neurodegenerative disorder, marked by the degeneration of dopamine (DA) neurons in the substantia nigra (SN). Current evidence strongly suggests that neuroinflammation, primarily mediated by microglia, contributes to PD pathogenesis. Triggering receptor expressed on myeloid cells 2 (TREM2) might serve as a promising therapeutic target for PD due to its ability to suppress neuroinflammation. Dihydroquercetin (DHQ) is an important natural dihydroflavone and confers apparent anti-inflammatory, antioxidant and anti-fibrotic effects. Recently, DHQ-mediated neuroprotection was exhibited. However, the specific mechanisms of its neuroprotective effects remain incompletely elucidated. METHODS: In this study, rat models were utilized to induce damage to DA neurons using lipopolysaccharide (LPS) and 6-hydroxydopamine (6-OHDA) to assess the impacts of DHQ on the loss of DA neurons. Furthermore, DA neuronal MN9D cells and microglial BV2 cells were employed to investigate the function of TREM2 in DHQ-mediated DA neuroprotection. Finally, TREM2 knockout mice were used to investigate whether the neuroprotective effects mediated by DHQ through a mechanism dependent on TREM2. RESULTS: The main findings demonstrated that DHQ effectively protected DA neurons against neurotoxicity induced by LPS and 6-OHDA and inhibited microglia-elicited neuroinflammation. Meanwhile, DHQ promoted microglial TREM2 signaling activation. Notably, DHQ failed to reduce inflammatory cytokines release and further present neuroprotection from DA neurotoxicity upon TREM2 silencing. Similarly, DHQ didn't exert DA neuroprotection in TREM2 knockout mice. CONCLUSIONS: These findings suggest that DHQ exerted DA neuroprotection by regulating microglia TREM2 activation.

Nasal application of kisspeptin-54 mitigates motor deficits by reducing nigrostriatal dopamine loss in hemiparkinsonian rats.

Parkinson's Disease is a progressive neurodegenerative disorder characterized by motor symptoms resulting from the loss of nigrostriatal dopaminergic neurons. Kisspeptins (KPs) are a family of neuropeptides that are encoded by the Kiss-1 gene, which exert their physiological effects through interaction with the GPR54 receptor. In the current investigation, we investigated the prospective protective effects of central KP-54 treatments on nigrostriatal dopaminergic neurons and consequent motor performance correlates in 6-hydroxydopamine (6-OHDA)-lesioned rats. Male adult Sprague Dawley rats underwent stereotaxic injection of 6-OHDA into the right medial forebrain bundle to induce hemiparkinsonism. Following surgery, rats received chronic central treatments of nasal or intracerebroventricular KP-54 (logarithmically increasing doses) for seven consecutive days. Motor performance was evaluated seven days post-surgery utilizing the open field test and catalepsy test. The levels of dopamine in the striatum were determined with mass spectrometry. Immunohistochemical analysis was conducted to assess the immunoreactivities of tyrosine hydroxylase (TH) and the GPR54 in the substantia nigra. The dose-response curve revealed a median effective dose value of ≈3 nmol/kg for both central injections. Due to its non-invasive and effective nature, nasal administration was utilized in the second phase of our study. Chronic administration of KP-54 (3nmol/kg, nasally) significantly protected 6-OHDA-induced motor deficits. Nasal KP-54 attenuated the loss of nigrostriatal dopaminergic neurons induced by 6-OHDA. Additionally, significant correlations were observed between motor performance and nigrostriatal dopamine levels. Immunohistochemical analysis demonstrated the localization of the GPR54 within TH-positive nigral cells. These findings suggest the potential efficacy of central KP-54 on motor impairments in hemiparkinsonism.

Exploring the complex interplay between Parkinson's disease and BAG proteins.

Parkinsons disease (PD) is a chronic fast growing neurodegenerative disorder of Central Nervous System (CNS) characterized by progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and formation of Lewy bodies (LBs) which causes dopamine deficiency within basal ganglia leading to motor and non-motor manifestation. According to reports, many factors are responsible for pathogenesis of PD which includes environmental factors, genetic factors, and aging factors. Whereas death of dopaminergic neurons is also caused by oxidative stress, neuroinflammation, and autophagy disorder. Molecular chaperones/co-chaperones are proteins that binds to an unstable conformer of another protein and stabilizes it. Chaperones prevent incorrect interaction between non-native polypeptides which increases the yield but not the rate of reaction. The Bcl-2-associated athanogene (BAG) is a multifunctional group of proteins belonging to BAG family of co-chaperones. Recent studies demonstrates that chaperones interact with PD-related proteins. Co-chaperones like BAG family proteins regulate the function of chaperones. Molecular chaperones regulate the mitochondrial functions by interacting with the PD-related proteins associated with it. This review studies the contribution of chaperones and PD-related proteins in pathogenesis of PD aiming to provide an alternate molecular target for preventing the disease progression.

Distinct µ-opioid ensembles trigger positive and negative fentanyl reinforcement.

Fentanyl is a powerful painkiller that elicits euphoria and positive reinforcement1. Fentanyl also leads to dependence, defined by the aversive withdrawal syndrome, which fuels negative reinforcement2,3 (that is, individuals retake the drug to avoid withdrawal). Positive and negative reinforcement maintain opioid consumption, which leads to addiction in one-fourth of users, the largest fraction for all addictive drugs4. Among the opioid receptors, µ-opioid receptors have a key role5, yet the induction loci of circuit adaptations that eventually lead to addiction remain unknown. Here we injected mice with fentanyl to acutely inhibit γ-aminobutyric acid-expressing neurons in the ventral tegmental area (VTA), causing disinhibition of dopamine neurons, which eventually increased dopamine in the nucleus accumbens. Knockdown of µ-opioid receptors in VTA abolished dopamine transients and positive reinforcement, but withdrawal remained unchanged. We identified neurons expressing µ-opioid receptors in the central amygdala (CeA) whose activity was enhanced during withdrawal. Knockdown of µ-opioid receptors in CeA eliminated aversive symptoms, suggesting that they mediate negative reinforcement. Thus, optogenetic stimulation caused place aversion, and mice readily learned to press a lever to pause optogenetic stimulation of CeA neurons that express µ-opioid receptors. Our study parses the neuronal populations that trigger positive and negative reinforcement in VTA and CeA, respectively. We lay out the circuit organization to develop interventions for reducing fentanyl addiction and facilitating rehabilitation.