Journal of Neuroscience最新文献

{"title":"Neural correlates of perceptual plasticity in the auditory midbrain and thalamus.","authors":"Rose Ying, Daniel J Stolzberg, Melissa L Caras","doi":"10.1523/JNEUROSCI.0691-24.2024","DOIUrl":"https://doi.org/10.1523/JNEUROSCI.0691-24.2024","url":null,"abstract":"<p><p>Hearing is an active process in which listeners must detect and identify sounds, segregate and discriminate stimulus features, and extract their behavioral relevance. Adaptive changes in sound detection can emerge rapidly, during sudden shifts in acoustic or environmental context, or more slowly as a result of practice. Although we know that context- and learning-dependent changes in the sensitivity of auditory cortical (ACX) neurons support many aspects of perceptual plasticity, the contribution of subcortical auditory regions to this process is less understood. Here, we recorded single- and multi-unit activity from the central nucleus of the inferior colliculus (ICC) and the ventral subdivision of the medial geniculate nucleus (MGV) of male and female Mongolian gerbils under two different behavioral contexts: as animals performed an amplitude modulation (AM) detection task and as they were passively exposed to AM sounds. Using a signal detection framework to estimate neurometric sensitivity, we found that neural thresholds in both regions improved during task performance, and this improvement was largely driven by changes in firing rate rather than phase locking. We also found that ICC and MGV neurometric thresholds improved as animals learn to detect small AM depths during a multi-day perceptual training paradigm. Finally, we reveal that in the MGV, but not the ICC, context-dependent enhancements in AM sensitivity grow stronger during perceptual training, mirroring prior observations in the ACX. Together, our results suggest that the auditory midbrain and thalamus contribute to changes in sound processing and perception over rapid and slow timescales.<b>Significance statement</b> What a listener hears depends on several factors, such as whether the listener is attentive or distracted, and whether the sound is meaningful or irrelevant. Practice can also shape hearing by improving the detection of particular sound features, as occurs during language or musical learning. Understanding how changes in sound perception arise in the brain is important for developing strategies to optimize healthy hearing, and for treating disorders in which these processes go awry. We report that neurons in the auditory midbrain and thalamus exhibit rapid shifts in sound sensitivity that depend on the sound's behavioral relevance, and slower improvements that emerge over several days of training. Our results suggest that subcortical areas make an important contribution to flexible hearing.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142928130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adolescent cerebellar nuclei manipulation alters reversal learning and perineuronal net intensity independently in male and female mice.","authors":"Tristan T Lyle, Jessica L Verpeut","doi":"10.1523/JNEUROSCI.2182-23.2024","DOIUrl":"https://doi.org/10.1523/JNEUROSCI.2182-23.2024","url":null,"abstract":"<p><p>The cerebellum, identified to be active during cognitive and social behavior, has multisynaptic connections through the cerebellar nuclei (CN) and thalamus to cortical regions, yet formation and modulation of these pathways are not fully understood. Perineuronal nets (PNNs) respond to changes in local cellular activity and emerge during development. PNNs are implicated in learning and neurodevelopmental disorders, but their role in the CN during development is unknown. Connectivity deficits, specifically between lateral CN (LCN)-cortical regions have been found in autism spectrum disorder (ASD) with patients displaying reduced cognitive flexibility.To examine the role of LCN on cognition, neural activity was perturbed in both male and female mice using Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) from postnatal day 21-35. We found that while an adolescent LCN disruption did not alter task acquisition, correct choice reversal performance was dependent on DREADD manipulation and sex. Inhibitory DREADDs improved reversal learning in males (5 days faster to criteria) and excitatory DREADDs improved female reversal learning (10 days faster to criteria) compared to controls. Interestingly, the DREADD manipulation in females regardless of direction, reduced PNN intensity, whereas in males only the inhibitory DREADDS reduced PNNs. This suggests a chronic adolescent LCN manipulation may have sex-specific compensatory changes in PNN structure and LCN output to improve reversal learning. This study provides new evidence for LCN in non-motor functions and sex-dependent differences in behavior and CN plasticity.<b>Significance statement</b> The cerebellum is commonly known to be important for motor control; however, recent studies have revealed a role in cognition. Yet, it is unknown if the cerebellum modulates cognition in early development or the pathways by which this influence may be exerted. Using a chemogenetic approach, we manipulated the lateral cerebellar nuclei in adolescent male and female mice. Flexible cognition, measured through reversal learning of a touchscreen task was altered in a sex-dependent way. Perineuronal nets were found to be reduced in mice with a cerebellar nuclei DREADD inhibition and these mice demonstrated faster reversal learning. These findings highlight the importance of studying the cerebellar nuclei to gain new insights into early development.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142928703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disruption of extracellular matrix and perineuronal nets modulates extracellular space volume and geometry.","authors":"Eva Syková, Ivan Voříšek, Zenon Starčuk, Jiří Kratochvíla, Iveta Pavlova, Yuki Ichikawa, Jessica C F Kwok, Eva Kmoníčková, Svitlana Myronchenko, Tomáš Hromádka, Tomáš Smolek, Martin Avila, Neha Basheer, Norbert Žilka","doi":"10.1523/JNEUROSCI.0517-24.2024","DOIUrl":"https://doi.org/10.1523/JNEUROSCI.0517-24.2024","url":null,"abstract":"<p><p>Extracellular matrix (ECM) is a network of macromolecules which has two forms - perineuronal nets (PNNs) and a diffuse ECM (dECM) - both influence brain development, synapse formation, neuroplasticity, CNS injury and progression of neurodegenerative diseases. ECM remodeling can influence extrasynaptic transmission, mediated by diffusion of neuroactive substances in the extracellular space (ECS). In this study we analyzed how disrupted PNNs and dECM influence brain diffusibility. Two months after oral treatment of rats with 4-methylumbelliferone (4-MU), an inhibitor of hyaluronan synthesis, we found downregulated staining for PNNs, hyaluronan, chondroitin sulphate proteoglycans and glial fibrillary acidic protein (GFAP). These changes were enhanced after 4 and 6 months and were reversible after normal diet. Morphometric analysis further indicated atrophy of astrocytes. Using real-time iontophoretic method dysregulation of ECM resulted in increased ECS volume fraction α in somatosensory cortex (SC) by 35 %, from α = 0.20 in control rats to α = 0.27 after the 4-MU diet. Diffusion-weighted magnetic resonance imaging (DW-MRI) revealed a decrease of mean diffusivity (MD) and fractional anisotropy (FA) in the cortex, hippocampus, thalamus, pallidum and spinal cord. This study shows the increase in ECS volume, a loss of FA and changes in astrocytes due to modulation of PNNs and dECM that could affect extrasynaptic transmission, cell to cell communication and neural plasticity.<b>Significance Statement</b> Inhibition of hyaluronan synthesis induced by oral treatment with 4-methylumebelliferone disrupts perineuronal nets (PNNs), diffuse extracellular matrix (dECM), reduces the astrocytic network, increases extracellular space (ECS) volume and changes ECS geometry. The changes of diffusion barriers significantly affect diffusion parameters in the adult brain and spinal cord. Our findings suggest that disruption of ECM allows for more efficient transport of ions, neurotransmitters and neuroactive substances in the ECS and thus ensures broader inter-neuronal communication by extrasynaptic transmission. Disruption of PNNs and an increase in ECS volume can result in enhanced crosstalk between synapses, spill-over of transmitters, formation of new synaptic contacts and thus increased synaptic plasticity.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142928706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of differential sublaminar feedforward inhibitory circuits in CA1 hippocampus requires <i>Satb2</i>.","authors":"Meretta A Hanson, Noor Bibi, Alireza Safa, Devipriyanka Nagarajan, Alec H Marshall, Aidan C Johantges, Jason C Wester","doi":"10.1523/JNEUROSCI.0737-24.2024","DOIUrl":"10.1523/JNEUROSCI.0737-24.2024","url":null,"abstract":"<p><p>Pyramidal cells (PCs) in CA1 hippocampus can be classified by their radial position as deep or superficial and organize into subtype-specific circuits necessary for differential information processing. Specifically, superficial PCs receive fewer inhibitory synapses from parvalbumin (PV)-expressing interneurons than deep PCs, resulting in weaker feedforward inhibition of input from CA3 Schaffer collaterals. Using mice, we investigated mechanisms underlying CA1 PC differentiation and the development of this inhibitory circuit motif. We found that the transcriptional regulator SATB2, which is necessary for pyramidal cell differentiation in the neocortex, is selectively expressed in superficial PCs during early postnatal development. To investigate its role in CA1, we conditionally knocked out <i>Satb2</i> from pyramidal cells during embryonic development using both male and female Emx1^IRES-Cre;Satb2^flox/flox mice. Loss of <i>Satb2</i> resulted in increased feedforward inhibition of CA3 Schaffer collateral input to superficial PCs, which matched that observed to deep PCs in control mice. Using paired whole-cell recordings between PCs and PV+ interneurons, we found this was due to an increase in the strength of unitary inhibitory synaptic connections from PV+ interneurons to mutant superficial PCs. Regulation of synapse strength was restricted to inhibitory synapses; excitatory synaptic connections from CA3 to CA1 PCs and from CA1 PCs to PV+ interneurons were not affected by loss of <i>Satb2</i> Finally, we show that SATB2 expression in superficial PCs is necessary to suppress the formation of synapses from PV+ interneurons during synaptogenesis. Thus, early postnatal expression of SATB2 in superficial PCs is necessary for the development of biased feedforward inhibition in CA1.<b>Significance statement</b> Deep and superficial pyramidal cells (PCs) in CA1 hippocampus are distinct subtypes that integrate into separate circuits to provide unique hippocampal computations to the rest of the brain. The mechanisms that determine the identity and circuit integration of each PC subtype are unclear. Here, we show that expression of the transcriptional regulator <i>Satb2</i> in superficial PCs is necessary to suppress the formation of inhibitory synapses from PV+ interneurons during early development. This is critical to reduce feedforward inhibition of CA3 Schaffer collateral input to superficial PCs relative to deep PCs in mature circuits. Our data provide insight into the development of cell-type-specific circuits in the hippocampus, which is crucial for determining how they function to support learning and memory.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142928705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synaptic Vesicle glycoprotein 2A knockout in parvalbumin and somatostatin interneurons drives seizures in the postnatal mouse brain.","authors":"Odile Bartholome, Virginie Neirinckx, Orianne De La Brassinne, Jana Desloovere, Priscilla Van Den Ackerveken, Robrecht Raedt, Bernard Rogister","doi":"10.1523/JNEUROSCI.1169-24.2024","DOIUrl":"https://doi.org/10.1523/JNEUROSCI.1169-24.2024","url":null,"abstract":"<p><p>Synaptic vesicle glycoprotein 2A (SV2A) is a presynaptic protein targeted by the antiseizure drug levetiracetam. One or more of the three SV2 genes is expressed in all neurons and is essential to normal neurotransmission. Loss of SV2A results in a seizure phenotype in mice and mutations in humans are also linked to congential seizures. How affecting SV2A action impacts the epileptic phenotype remains unclear, especially among the diverse neuronal populations that regulate network excitability. This study explored how brain structure and function are affected by SV2A conditional knock-out (SV2A-cKO) in specific neural cell subtypes. We show that SV2A-cKO in all neurons of the postnatal brain triggers lethal seizures, suggesting that the seizures observed in earlier knockout models were not due to aberrant brain development. Similar lethal seizures are detected in mice in which the loss of SV2A is limited to GABAergic neurons, whereas loss in excitatory neurons produces no noticeable phenotype. No apparent gender difference was ever observed. Further investigation revealed that SV2A-cKO in different GABAergic interneuron populations induces seizure, with variable timescales and severity. Most notably SV2A-cKO in parvalbumin interneurons (PV+) leads to lethal seizures in young animals, while SV2A-cKO in somatostatin (SST) inhibitory neurons results in seizures that were scarcely observed only in adult mice. These results support the crucial role SV2A plays in PV and SST interneurons and suggest that the action of Levetiracetam may be due largely to effects on a subset of GABAergic interneurons.<b>Significance statement</b> The synaptic vesicle glycoprotein 2A is the target of the antiseizure drug levetiracetam, and the SV2A full knockout in mice induce severe seizures. Still, SV2A function in synapses is yet not fully elucidated, including the neuronal subtypes in which SV2A expression is mandatory or dispensable. In this paper, we demonstrated that SV2A knockout in inhibitory neurons provokes seizure (incl. PV+ and SST+) whereas it does not induce any visible phenotype in excitatory neurons. Our study supports the key role of SV2A in interneuron populations, in the context of epilepsy.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142928247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Compromising tyrosine hydroxylase function extends and blunts the temporal profile of reinforcement by dopamine neurons in <i>Drosophila</i>.","authors":"Fatima Amin, Christian König, Jiajun Zhang, Liubov S Kalinichenko, Svea Königsmann, Vivian Brunsberg, Thomas D Riemensperger, Christian P Müller, Bertram Gerber","doi":"10.1523/JNEUROSCI.1498-24.2024","DOIUrl":"https://doi.org/10.1523/JNEUROSCI.1498-24.2024","url":null,"abstract":"<p><p>For a proper representation of the causal structure of the world, it is adaptive to consider both evidence for and evidence against causality. To take punishment as an example, the causality of a stimulus is unlikely if there is a temporal gap before punishment is received, but causality is credible if the stimulus immediately precedes punishment. In contrast, causality can be ruled out if the punishment occurred first. At the behavioral level, this is reflected in the associative principle of timing-dependent valence reversal: aversive memories are formed when a stimulus occurs before the punishment, whereas memories of appetitive valence are formed when a stimulus is presented upon the relieving termination of punishment. We map the temporal profile of memories induced by optogenetic activation of the PPL1-01 neuron in the fly <i>Drosophila melanogaster</i> (of either sex), and find that compromising tyrosine hydroxylase function, either acutely by pharmacological methods or by cell-specific RNAi, extends and blunts this profile. Specifically, it i) enhances learning with a time gap between the stimulus and PPL1-01 punishment (better trace conditioning), ii) impairs learning when the stimulus immediately precedes PPL1-01 punishment (worse delay conditioning), and iii) prevents learning about a stimulus presented after PPL1-01 punishment has ceased (worse relief conditioning). Under conditions of low dopamine, we furthermore observe a role for serotonin that is pronounced in trace conditioning, weaker in delay conditioning, and absent in relief conditioning. We discuss the psychiatric implications if related alterations in the temporal profile of reinforcement were to occur in humans.<b>Significance statement</b> Acting in conformity with the causal structure of the world is important for survival in animals and humans alike. To do so, it is crucial to consider both evidence for and evidence against causality. For example, the causality of a stimulus is a reasonable assumption if it precedes punishment, whereas causality can be ruled out if the punishment occurred first. This is reflected in the opposite memories that are established through the 'bad' occurrence versus the 'good' termination of punishment. We find in the fruit fly <i>Drosophila melanogaster</i> that compromising dopamine synthesis establishes a distortion of these processes and discuss the psychiatric implications if such distortions were to occur in humans.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142928704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microvascular dysfunction, mitochondrial reprogramming, and inflammasome activation as critical regulators of ischemic stroke severity induced by chronic exposure to prescription opioids.","authors":"Enze Sun, Silvia Torices, Olivia M Osborne, Michal Toborek","doi":"10.1523/JNEUROSCI.0614-24.2024","DOIUrl":"https://doi.org/10.1523/JNEUROSCI.0614-24.2024","url":null,"abstract":"<p><p>The opioid epidemic endangers not only public health but also social and economic welfare. Growing clinical evidence indicates that chronic use of prescription opioids may contribute to an elevated risk of ischemic stroke and negatively impact post-stroke recovery. In addition, NLRP3 inflammasome activation has been related to several cerebrovascular diseases, including ischemic stroke. Interestingly, an increase in NLRP3 inflammasome activation has also been reported in chronic opioid exposure. Given the pivotal roles of the blood-brain barrier (BBB) and oxidative stress in ischemic stroke pathophysiology, this study focuses on the impact of chronic exposure to prescription opioids on the integrity of cerebrovascular microvasculature, endothelial mitochondrial homeostasis, and the outcomes of ischemic stroke in male wild type and NLRP3-deficient mice. Our results demonstrate that chronic opioid exposure can compromise the integrity of the BBB and elevate the generation of reactive oxygen species (ROS), resulting in endothelial mitochondrial dysfunction and apoptosis activation. We also provide evidence that opioid exposure enhances inflammasome activation, inflammatory responses, and increases the severity of an ischemic stroke. The antioxidant N-acetylcysteine (NAC) ameliorated these opioid-induced alterations and accelerated the post-stroke tissue restoration and functional recovery processes in opioid-exposed mice. Importantly, there was also a significant decrease in ischemic stroke damage in the NLRP3-deficient mice with chronic opioid exposure as compared to wild-type controls. These findings indicate that chronic exposure to prescription opioids impacts the outcome of ischemic stroke by damaging microvascular cerebral integrity through inflammasome activation and mitochondrial dysfunction.<b>Significance Statement</b> Misuse of opioids has become one of the most important public health problems. Growing evidence indicates that chronic use of prescription opioids may contribute to an elevated risk of ischemic stroke, and negatively impact post-stroke recovery. In the present study, we hypothesize that microvascular dysfunction can underlie the impact of prescription opioid on an ischemic stroke. Our novel results demonstrate that opioid exposure leads to mitochondrial dysfunction in the brain microvascular endothelium, compromised blood-brain barrier integrity, enhanced inflammatory responses, and more severe effects of an ischemic stroke. Importantly, the NLRP3 inflammasome-deficient mice or treatment with N-acetylcysteine attenuated these alterations and enhanced post-stroke tissue and functional recovery, providing valuable therapeutic options for people with opioid use disorder.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142927813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-nuclei sequencing reveals a robust corticospinal response to nearby axotomy but overall insensitivity to spinal injury.","authors":"Zimei Wang, Manojkumar Kumaran, Elizabeth Batsel, Sofia Testor-Cabrera, Zac Beine, Alicia Alvarez Ribelles, Pantelis Tsoulfas, Ishwariya Venkatesh, Murray G Blackmore","doi":"10.1523/JNEUROSCI.1508-24.2024","DOIUrl":"https://doi.org/10.1523/JNEUROSCI.1508-24.2024","url":null,"abstract":"<p><p>The ability of neurons to sense and respond to damage is crucial for maintaining homeostasis and facilitating nervous system repair. For some cell types, notably dorsal root ganglia (DRG) and retinal ganglion cells (RGCs), extensive profiling has uncovered a significant transcriptional response to axon injury, which influences survival and regenerative outcomes. In contrast, the injury responses of most supraspinal cell types, which display limited regeneration after spinal damage, remain mostly unknown. In this study, we used single-nuclei sequencing in adult male and female mice to profile the transcriptional responses of diverse supraspinal cell types to spinal injury. Surprisingly, thoracic spinal injury induced only modest changes in gene expression across all populations, including corticospinal tract (CST) neurons. Additionally, CST neurons exhibited minimal response to cervical injury but showed much stronger reaction to intracortical axotomy, with upregulation of numerous regeneration and apoptosis-related transcripts shared with injured DRG and RGC neurons. Thus, the muted response of CST neuron to spinal injury is linked to the injury's distal location, rather than intrinsic cellular characteristics. More broadly, these findings indicate that a central challenge for enhancing regeneration after a spinal injury is the limited detection of distant injuries and the subsequent modest baseline neuronal response.<b>Significance statement</b> The inability of axons to regenerate after spinal injury limits functional recovery. Efforts to improve regeneration rely on a precise understanding of the baseline transcriptional response to spinal injury. Through single-nuclei sequencing of diverse descending cell types, we find that spinal injury causes only modest changes in gene expression, whereas axon damage close to cell bodies elicits a much larger response. These findings highlight the muted detection of distant injury, and the subsequent failure to initiate widespread gene expression changes, as major obstacles to axon regeneration after spinal injury.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142922082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dopamine boosts motivation for prosocial effort in Parkinson's disease.","authors":"Jamie Talbot, Jo Cutler, Marin Tamm, Simon J Little, Catherine J Harmer, Masud Husain, Patricia L Lockwood, Matthew A J Apps","doi":"10.1523/JNEUROSCI.1593-24.2024","DOIUrl":"https://doi.org/10.1523/JNEUROSCI.1593-24.2024","url":null,"abstract":"<p><p>Being willing to exert effort to obtain rewards is a key component of motivation. Previous research has shown that boosting dopamine can increase the willingness to choose to exert effort to obtain rewards for ourselves. Yet often we must choose whether to exert effort, not for our own immediate benefit, but to be prosocial and obtain a benefit for someone else. Pharmacologically increasing dopamine availability has been shown to change social behaviours in experimental tasks, and dopamine degeneration in Parkinson's Disease (PD) impacts a range of socio-cognitive processes. However, the neuromodulators involved in deciding whether to exert effort to benefit others are unknown. Does dopamine modulate the willingness to exert prosocial effort? Here, male and female PD patients (n=37) ON or OFF their dopaminergic medication completed a task where they chose whether to put in effort for larger reward, or rest and receive a smaller reward, on separate trials either to benefit themselves ('self') or an anonymous other person ('other'). PD patients were more willing to exert effort to benefit themselves than another person, a pattern also observed in an age- and gender-matched control group (n=42). However, crucially PD patients had increased willingness to exert effort for other relative to self, ON compared to OFF medication. These results suggest that dopamine augmentation in PD can increase levels of prosocial motivation, highlighting a key role for dopamine in motivation beyond obtaining rewards for ourselves.<b>Significance Statement</b> Prosocial behaviours - acts that benefit other people - are fundamental for societal cohesion. Often prosocial acts, such as helping a friend move home, are effortful. However, the neurochemicals involved in choosing to put effort into prosocial acts are unknown. Dopamine is involved in motivating people to exert effort to obtain themselves rewards, but does it also make us choose to put more effort into prosocial behaviours? We find that dopamine depleted Parkinson's Disease patients are more willing to choose to put effort into prosocial acts ON dopamine boosting medication compared to OFF. These results provide the first insight into the neurochemicals underlying prosocial effort, and highlight dopamine as key to working hard to help others.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142923856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Melanin concentrating hormone projections to the nucleus accumbens enhance the reward value of food consumption and do not induce feeding or REM sleep.","authors":"Katherine L Furman, Lorelei Baron, Hannah C Lyons, Timothy Cha, Jack R Evans, Jayeeta Manna, Limei Zhu, Joanna Mattis, Christian R Burgess","doi":"10.1523/JNEUROSCI.1725-24.2024","DOIUrl":"https://doi.org/10.1523/JNEUROSCI.1725-24.2024","url":null,"abstract":"<p><p>Regulation of food intake and energy balance is critical to survival. Hunger develops as a response to energy deficit and drives food-seeking and consumption. However, motivations to eat are varied in nature, and promoted by factors other than energy deficit. When dysregulated, non-homeostatic drives to consume can contribute to disorders of food intake, adding to the increasing prevalence of restrictive eating disorders and obesity. Melanin-concentrating hormone (MCH) neurons have been implicated in the regulation of feeding behavior, in addition to a number of other fundamental behaviors including sleep, anxiety, and maternal behavior. Several studies suggest that MCH peptide increases food consumption, while studies of MCH neurons show effects only on cued feeding, and others show no effect of MCH neuron manipulation on feeding. MCH neurons have widespread projections to diverse downstream brain regions yet few studies have investigated the function of specific projections or differentiated the behaviors they regulate. Here we use optogenetics, in combination with different behavioral paradigms, to elucidate the role of MCH projections to the nucleus accumbens (NAc) in sleep and feeding behavior. We show that MCH neurons projecting to the NAc do not induce changes in baseline feeding or REM sleep, but do enhance the preference for a food paired with optogenetic stimulation. Furthermore, this effect is diminished in female mice relative to males, in line with previous results suggesting sex differences in the functional role of MCH neurons. These results suggest that MCH projections to the NAc can enhance the rewarding value of consumed food.<b>Significance Statement</b> While feeding is often driven by hunger, there are non-homeostatic reasons why animals consume food. Melanin-concentrating hormone (MCH) neurons have been implicated in the regulation of many fundamental behaviors, including feeding, sleep and reward. They project broadly throughout the brain, suggesting that they may mediate this diverse set of behaviors independently via specific projections to downstream regions. We used optogenetic activation of MCH neurons and their projections to the nucleus accumbens (NAc) in combination with complex behavioral paradigms to demonstrate that MCH projections to the NAc do not induce baseline feeding or increases in REM sleep but do enhance the value of a paired food. These results suggest that MCH neurons contribute to non-homeostatic consumption via projections to the NAc.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142923899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}