Pub Date : 2024-07-09DOI: 10.1523/jneurosci.1108-24.2024
{"title":"Erratum: Schlüter et al., “Rabphilin Knock-Out Mice Reveal That Rabphilin Is Not Required for Rab3 Function in Regulating Neurotransmitter Release”","authors":"","doi":"10.1523/jneurosci.1108-24.2024","DOIUrl":"https://doi.org/10.1523/jneurosci.1108-24.2024","url":null,"abstract":"","PeriodicalId":22786,"journal":{"name":"The Journal of Neuroscience","volume":"109 38","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141665873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Memory formation requires coordinated control of gene expression, protein synthesis, and ubiquitin-proteasome system- (UPS-) mediated protein degradation. The catalytic component of the UPS, the 26S proteasome, contains a 20S catalytic core surrounded by two 19S regulatory caps and phosphorylation of 19S cap regulatory subunit RPT6 at serine 120 (pRPT6-S120) has been widely implicated in controlling activity-dependent increases in proteasome activity. Recently, RPT6 was also shown to act outside the proteasome where it has a transcription factor-like role in the hippocampus during memory formation. However, little is known about the proteasome-independent function of “free” RPT6 in the brain or during memory formation and whether phosphorylation of S120 is required for this transcriptional control function. Here, we used RNA-sequencing along with novel genetic approaches and biochemical, molecular, and behavioral assays to test the hypothesis that pRPT6-S120 functions independently of the proteasome to bind DNA and regulate gene expression during memory formation. RNA-sequencing following siRNA-mediated knockdown of free RPT6 revealed 46 gene targets in the dorsal hippocampus of male rats following fear conditioning, where RPT6 was involved in transcriptional activation and repression. Through CRISPR-dCas9-mediated artificial placement of RPT6 at a target gene, we found that RPT6 DNA binding alone may be important for altering gene expression following learning. Further, CRISPR-dCas13-mediated conversion of S120 to glycine on RPT6 revealed that phosphorylation at S120 is necessary for RPT6 to bind DNA and properly regulate transcription during memory formation. Together, we reveal a novel function for phosphorylation of RPT6 in controlling gene transcription during memory formation.Significance StatementThe role of the proteasome subunit RPT6, particularly when phosphorylated at serine 120 (pRPT6-S120), has been extensively studied in the context of proteasome-mediated protein degradation, but its role in regulating gene expression during memory formation has not been explored. This study identifies gene targets of RPT6 during memory formation and reveals that the presence of RPT6 alone at DNA may cause changes in gene expression. Further, we found that pRPT6-S120 was necessary for DNA binding and transcriptional regulation during memory formation. Considering the popularity of proteasome-inhibiting drugs, these data are noteworthy for the neuroscience community as they demonstrate a clear role for proteasome-independent RPT6 in transcriptional regulation of gene expression during memory formation, which is dysregulated when RPT6 is manipulated.
{"title":"Phosphorylation of RPT6 controls its ability to bind DNA and regulate gene expression in the hippocampus of male rats during memory formation","authors":"Kayla Farrell, Aubrey Auerbach, Madeline Musaus, Shaghayegh Navabpour, Catherine Liu, Yu Lin, Hehuang Xie, Timothy J. Jarome","doi":"10.1523/jneurosci.1453-23.2023","DOIUrl":"https://doi.org/10.1523/jneurosci.1453-23.2023","url":null,"abstract":"Memory formation requires coordinated control of gene expression, protein synthesis, and ubiquitin-proteasome system- (UPS-) mediated protein degradation. The catalytic component of the UPS, the 26S proteasome, contains a 20S catalytic core surrounded by two 19S regulatory caps and phosphorylation of 19S cap regulatory subunit RPT6 at serine 120 (pRPT6-S120) has been widely implicated in controlling activity-dependent increases in proteasome activity. Recently, RPT6 was also shown to act outside the proteasome where it has a transcription factor-like role in the hippocampus during memory formation. However, little is known about the proteasome-independent function of “free” RPT6 in the brain or during memory formation and whether phosphorylation of S120 is required for this transcriptional control function. Here, we used RNA-sequencing along with novel genetic approaches and biochemical, molecular, and behavioral assays to test the hypothesis that pRPT6-S120 functions independently of the proteasome to bind DNA and regulate gene expression during memory formation. RNA-sequencing following siRNA-mediated knockdown of free RPT6 revealed 46 gene targets in the dorsal hippocampus of male rats following fear conditioning, where RPT6 was involved in transcriptional activation and repression. Through CRISPR-dCas9-mediated artificial placement of RPT6 at a target gene, we found that RPT6 DNA binding alone may be important for altering gene expression following learning. Further, CRISPR-dCas13-mediated conversion of S120 to glycine on RPT6 revealed that phosphorylation at S120 is necessary for RPT6 to bind DNA and properly regulate transcription during memory formation. Together, we reveal a novel function for phosphorylation of RPT6 in controlling gene transcription during memory formation.Significance StatementThe role of the proteasome subunit RPT6, particularly when phosphorylated at serine 120 (pRPT6-S120), has been extensively studied in the context of proteasome-mediated protein degradation, but its role in regulating gene expression during memory formation has not been explored. This study identifies gene targets of RPT6 during memory formation and reveals that the presence of RPT6 alone at DNA may cause changes in gene expression. Further, we found that pRPT6-S120 was necessary for DNA binding and transcriptional regulation during memory formation. Considering the popularity of proteasome-inhibiting drugs, these data are noteworthy for the neuroscience community as they demonstrate a clear role for proteasome-independent RPT6 in transcriptional regulation of gene expression during memory formation, which is dysregulated when RPT6 is manipulated.","PeriodicalId":22786,"journal":{"name":"The Journal of Neuroscience","volume":"79 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138586676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-08DOI: 10.1523/jneurosci.0869-23.2023
Di Liu, Su-Wan Hu, Di Wang, Qi Zhang, X. Zhang, H. Ding, Jun-Li Cao
The dorsal raphe nucleus (DRN) is an important nucleus in pain regulation. However, the underlying neural pathway and the function of specific cell types remain unclear. Here, we report a previously unrecognized ascending facilitation pathway, the DRN to mesoaccumbal dopamine (DA) circuit, for regulating pain. Chronic pain increased the activity of DRN glutamatergic, but not serotonergic, neurons projecting to the ventral tegmental area (VTA) (DRNGlu-VTA) in male mice. Optogenetic activation of DRNGlu-VTA circuit induced a pain-like response in naïve male mice and its inhibition produced analgesic effect in male mice with neuropathic pain. Furthermore, we discovered that DRN ascending pathway regulated pain through strengthened excitatory transmission onto the VTA DA neurons projecting to the ventral part of nucleus accumbens medial shell (vNAcMed), thereby activated the mesoaccumbal DA neurons. Correspondingly, optogenetic manipulation of this three-node pathway bilaterally regulated pain behaviors. These findings identified a DRN ascending excitatory pathway that is crucial for pain sensory processing, which can potentially be exploited toward targeting pain disorders.Significance StatementThe dorsal raphe nucleus (DRN) in the midbrain contributes to pain processing, yet the detailed cellular and circuitry mechanisms remain largely unknown. Here, we report that chronic pain increases the activity of a specific subpopulation of DRN glutamatergic neurons, which project to the ventral tegmental area (VTA). The elevated excitability of DRN glutamatergic neurons causes the increased excitatory inputs to VTA dopamine neurons that selectively innervate the ventral part of the nucleus accumbens medial shell (vNAcMed). Optogenetic activation of the DRN-VTA-vNAcMed pathway induced neuronal plasticity in the VTA and resulted in pain hypersensitivity. These findings shed light on how ascending DRN excitatory circuit is involved in the sensory modulation of pain.
{"title":"An Ascending Excitatory Circuit from the Dorsal Raphe for Sensory Modulation of Pain","authors":"Di Liu, Su-Wan Hu, Di Wang, Qi Zhang, X. Zhang, H. Ding, Jun-Li Cao","doi":"10.1523/jneurosci.0869-23.2023","DOIUrl":"https://doi.org/10.1523/jneurosci.0869-23.2023","url":null,"abstract":"The dorsal raphe nucleus (DRN) is an important nucleus in pain regulation. However, the underlying neural pathway and the function of specific cell types remain unclear. Here, we report a previously unrecognized ascending facilitation pathway, the DRN to mesoaccumbal dopamine (DA) circuit, for regulating pain. Chronic pain increased the activity of DRN glutamatergic, but not serotonergic, neurons projecting to the ventral tegmental area (VTA) (DRNGlu-VTA) in male mice. Optogenetic activation of DRNGlu-VTA circuit induced a pain-like response in naïve male mice and its inhibition produced analgesic effect in male mice with neuropathic pain. Furthermore, we discovered that DRN ascending pathway regulated pain through strengthened excitatory transmission onto the VTA DA neurons projecting to the ventral part of nucleus accumbens medial shell (vNAcMed), thereby activated the mesoaccumbal DA neurons. Correspondingly, optogenetic manipulation of this three-node pathway bilaterally regulated pain behaviors. These findings identified a DRN ascending excitatory pathway that is crucial for pain sensory processing, which can potentially be exploited toward targeting pain disorders.Significance StatementThe dorsal raphe nucleus (DRN) in the midbrain contributes to pain processing, yet the detailed cellular and circuitry mechanisms remain largely unknown. Here, we report that chronic pain increases the activity of a specific subpopulation of DRN glutamatergic neurons, which project to the ventral tegmental area (VTA). The elevated excitability of DRN glutamatergic neurons causes the increased excitatory inputs to VTA dopamine neurons that selectively innervate the ventral part of the nucleus accumbens medial shell (vNAcMed). Optogenetic activation of the DRN-VTA-vNAcMed pathway induced neuronal plasticity in the VTA and resulted in pain hypersensitivity. These findings shed light on how ascending DRN excitatory circuit is involved in the sensory modulation of pain.","PeriodicalId":22786,"journal":{"name":"The Journal of Neuroscience","volume":"56 26","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138588197","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-08DOI: 10.1523/jneurosci.0250-23.2023
Etienne Abassi, L. Papeo
Understanding social interaction requires processing social agents and their relationship. Latest results show that much of this process is visually solved: visual areas can represent multiple people encoding emergent information about their interaction that is not explained by the response to the individuals alone. A neural signature of this process is an increased response in visual areas, to face-to-face (seemingly interacting) people, relative to people presented as unrelated (back-to-back). This effect highlighted a network of visual areas for representing relational information.How is this network organized?Using functional MRI, we measured brain activity of healthy female and male humans (N=42), in response to images of two faces or two (head-blurred) bodies, facing toward or away from each other. Taking thefacing>non-facingeffect as signature of relation perception, we found that relations between faces and between bodies were coded in distinct areas, mirroring the categorical representation of faces and bodies in visual cortex. Additional analyses suggest the existence of a third network encoding relations between (non-social) objects. Finally, a separate occipitotemporal network showed generalization of relational information across body, face and non-social object dyads (multivariate-pattern classification analysis), revealing shared properties of relations across categories. In sum, beyond single entities, visual cortex encodes the relations that bind multiple entities into relationships; it does so in a category-selective fashion, thus respecting a general organizing principle of representation in high-level vision. Visual areas encoding visual relational information can reveal the processing of emergent properties of social (and non-social) interaction which trigger inferential processes.Significance statementUnderstanding social interaction requires representing the actors as well as the relation between them. We show that the earliest, rudimentary representation of a social interaction is formed in visual cortex. Using fMRI on healthy adults, we measured the brain responses to two faces or two (head-blurred) bodies, and found that, beyond representing faces and bodies, the visual cortex represents their relations, distinguishing between seemingly interacting (face-to-face) and non-interacting (back-to-back) faces/bodies. Moreover, we found that information about face and body relations is represented in separate networks, in line with the general organizing principle of categorical representation in visual cortex. The brain network encoding visual relational information may represent emergent properties of interacting people, which underlie the cognitive representation of social interaction.
{"title":"Category-selective representation of relationships in visual cortex","authors":"Etienne Abassi, L. Papeo","doi":"10.1523/jneurosci.0250-23.2023","DOIUrl":"https://doi.org/10.1523/jneurosci.0250-23.2023","url":null,"abstract":"Understanding social interaction requires processing social agents and their relationship. Latest results show that much of this process is visually solved: visual areas can represent multiple people encoding emergent information about their interaction that is not explained by the response to the individuals alone. A neural signature of this process is an increased response in visual areas, to face-to-face (seemingly interacting) people, relative to people presented as unrelated (back-to-back). This effect highlighted a network of visual areas for representing relational information.How is this network organized?Using functional MRI, we measured brain activity of healthy female and male humans (N=42), in response to images of two faces or two (head-blurred) bodies, facing toward or away from each other. Taking thefacing>non-facingeffect as signature of relation perception, we found that relations between faces and between bodies were coded in distinct areas, mirroring the categorical representation of faces and bodies in visual cortex. Additional analyses suggest the existence of a third network encoding relations between (non-social) objects. Finally, a separate occipitotemporal network showed generalization of relational information across body, face and non-social object dyads (multivariate-pattern classification analysis), revealing shared properties of relations across categories. In sum, beyond single entities, visual cortex encodes the relations that bind multiple entities into relationships; it does so in a category-selective fashion, thus respecting a general organizing principle of representation in high-level vision. Visual areas encoding visual relational information can reveal the processing of emergent properties of social (and non-social) interaction which trigger inferential processes.Significance statementUnderstanding social interaction requires representing the actors as well as the relation between them. We show that the earliest, rudimentary representation of a social interaction is formed in visual cortex. Using fMRI on healthy adults, we measured the brain responses to two faces or two (head-blurred) bodies, and found that, beyond representing faces and bodies, the visual cortex represents their relations, distinguishing between seemingly interacting (face-to-face) and non-interacting (back-to-back) faces/bodies. Moreover, we found that information about face and body relations is represented in separate networks, in line with the general organizing principle of categorical representation in visual cortex. The brain network encoding visual relational information may represent emergent properties of interacting people, which underlie the cognitive representation of social interaction.","PeriodicalId":22786,"journal":{"name":"The Journal of Neuroscience","volume":"6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138586592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-08DOI: 10.1523/jneurosci.1492-23.2023
Yihan Xie, J. Brynildsen, Kyle Windisch, J. Blendy
Opioid use disorder is a chronic, relapsing disease associated with persistent changes in brain plasticity. A common single nucleotide polymorphism (SNP) in the mu-opioid receptor gene,OPRM1A118G, is associated with altered vulnerability to opioid addiction. Reconfiguration of neuronal connectivity may explain dependence risk in individuals with this SNP. Mice with the equivalentOprm1variant, A112G, demonstrate sex-specific alterations in the rewarding properties of morphine and heroin. To determine whether this SNP influences network-level changes in neuronal activity we compared FOS expression in male and female mice that were opioid-naïve or opioid-dependent. Network analyses identified significant differences between the AA and GGOprm1genotypes. Based on several graph theory metrics, including small-world analysis and degree centrality, we show that GG females in the opioid-dependent state exhibit distinct patterns of connectivity compared to other groups of the same genotype. Using a network control theory approach, we identified key cortical brain regions that drive the transition between opioid-naïve and opioid-dependent brain states; however, these regions are less influential in GG females leading to 6-fold higher average minimum energy needed to transition from the acute to the dependent state. In addition, we found that the opioid-dependent brain state is significantly less stable in GG females compared to other groups. Collectively, our findings demonstrate sex and genotype-specific modifications in local, mesoscale, and global properties of functional brain networks following opioid exposure and provide a framework for identifying genotype differences in specific brain regions that play a role in opioid dependence.Significance StatementOpioid use disorder is moderately heritable, and the common mu-opioid receptor variant (OPRM1A118G) has been repeatedly associated with this disease. Opioid use liability is often higher in individuals with a history of chronic exposure and can be moderated by this SNP. Using a mouse model of theOprm1SNP, our work revealed opioid-induced differences in network connectivity between sexes and opioid dependence states in AA and GGOprm1mice. We also identified six (predominantly cortical) brain regions that strongly influence the transition to an opioid-dependent brain state. These data suggest potential brain regions that may be targeted using non-invasive therapeutic approaches such as repetitive Transcranial Magnetic Stimulation (rTMS) and could be useful to inform personalized treatment.
{"title":"Neural network connectivity following opioid dependence is altered by a common genetic variant in the mu-opioid receptor,OPRM1A118G","authors":"Yihan Xie, J. Brynildsen, Kyle Windisch, J. Blendy","doi":"10.1523/jneurosci.1492-23.2023","DOIUrl":"https://doi.org/10.1523/jneurosci.1492-23.2023","url":null,"abstract":"Opioid use disorder is a chronic, relapsing disease associated with persistent changes in brain plasticity. A common single nucleotide polymorphism (SNP) in the mu-opioid receptor gene,OPRM1A118G, is associated with altered vulnerability to opioid addiction. Reconfiguration of neuronal connectivity may explain dependence risk in individuals with this SNP. Mice with the equivalentOprm1variant, A112G, demonstrate sex-specific alterations in the rewarding properties of morphine and heroin. To determine whether this SNP influences network-level changes in neuronal activity we compared FOS expression in male and female mice that were opioid-naïve or opioid-dependent. Network analyses identified significant differences between the AA and GGOprm1genotypes. Based on several graph theory metrics, including small-world analysis and degree centrality, we show that GG females in the opioid-dependent state exhibit distinct patterns of connectivity compared to other groups of the same genotype. Using a network control theory approach, we identified key cortical brain regions that drive the transition between opioid-naïve and opioid-dependent brain states; however, these regions are less influential in GG females leading to 6-fold higher average minimum energy needed to transition from the acute to the dependent state. In addition, we found that the opioid-dependent brain state is significantly less stable in GG females compared to other groups. Collectively, our findings demonstrate sex and genotype-specific modifications in local, mesoscale, and global properties of functional brain networks following opioid exposure and provide a framework for identifying genotype differences in specific brain regions that play a role in opioid dependence.Significance StatementOpioid use disorder is moderately heritable, and the common mu-opioid receptor variant (OPRM1A118G) has been repeatedly associated with this disease. Opioid use liability is often higher in individuals with a history of chronic exposure and can be moderated by this SNP. Using a mouse model of theOprm1SNP, our work revealed opioid-induced differences in network connectivity between sexes and opioid dependence states in AA and GGOprm1mice. We also identified six (predominantly cortical) brain regions that strongly influence the transition to an opioid-dependent brain state. These data suggest potential brain regions that may be targeted using non-invasive therapeutic approaches such as repetitive Transcranial Magnetic Stimulation (rTMS) and could be useful to inform personalized treatment.","PeriodicalId":22786,"journal":{"name":"The Journal of Neuroscience","volume":"44 13","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138587297","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-07DOI: 10.1523/jneurosci.1171-23.2023
Xuan Li, Jiapeng You, Yidi Pan, Changbao Song, Hai-fu Li, Xuying Ji, F. Liang
Parvalbumin (PV) interneurons in the auditory cortex (AC) play a crucial role in shaping auditory processing, including receptive field formation, temporal precision enhancement, and gain regulation. PV interneurons are also the primary inhibitory neurons in the tail of the striatum (TS), which is one of the major descending brain regions in the auditory nervous system. However, the specific roles of TS-PV interneurons in auditory processing remain elusive. In this study, morphological and slice recording experiments in both male and female mice revealed that TS-PV interneurons, compared to AC-PV interneurons, were present in fewer numbers but exhibited longer projection distances, which enabled them to provide sufficient inhibitory inputs to spiny projection neurons (SPNs). Furthermore, TS-PV interneurons received dense auditory input from both the AC and medial geniculate body (MGB), particularly from the MGB, which rendered their auditory responses comparable to those of AC-PV interneurons. Optogenetic manipulation experiments demonstrated that TS-PV interneurons were capable of bidirectionally regulating the auditory responses of SPNs. Our findings suggest that PV interneurons can effectively modulate auditory processing in the TS and may play a critical role in auditory-related behaviors.Significance StatementPV interneurons are one of the main inhibitory cell types in the TS, even though they are relatively scarce. Currently, it remains unclear whether or to what extent these neurons contribute to auditory processing in the TS. Here, we demonstrated that optogenetic manipulation of PV neuron activity significantly altered the auditory responses of SPNs, providing valuable insights into the role of the TS PV interneurons in auditory processing and their potential role in auditory-related behaviors.
{"title":"Effective Regulation of Auditory Processing by Parvalbumin Interneurons in the Tail of the Striatum","authors":"Xuan Li, Jiapeng You, Yidi Pan, Changbao Song, Hai-fu Li, Xuying Ji, F. Liang","doi":"10.1523/jneurosci.1171-23.2023","DOIUrl":"https://doi.org/10.1523/jneurosci.1171-23.2023","url":null,"abstract":"Parvalbumin (PV) interneurons in the auditory cortex (AC) play a crucial role in shaping auditory processing, including receptive field formation, temporal precision enhancement, and gain regulation. PV interneurons are also the primary inhibitory neurons in the tail of the striatum (TS), which is one of the major descending brain regions in the auditory nervous system. However, the specific roles of TS-PV interneurons in auditory processing remain elusive. In this study, morphological and slice recording experiments in both male and female mice revealed that TS-PV interneurons, compared to AC-PV interneurons, were present in fewer numbers but exhibited longer projection distances, which enabled them to provide sufficient inhibitory inputs to spiny projection neurons (SPNs). Furthermore, TS-PV interneurons received dense auditory input from both the AC and medial geniculate body (MGB), particularly from the MGB, which rendered their auditory responses comparable to those of AC-PV interneurons. Optogenetic manipulation experiments demonstrated that TS-PV interneurons were capable of bidirectionally regulating the auditory responses of SPNs. Our findings suggest that PV interneurons can effectively modulate auditory processing in the TS and may play a critical role in auditory-related behaviors.Significance StatementPV interneurons are one of the main inhibitory cell types in the TS, even though they are relatively scarce. Currently, it remains unclear whether or to what extent these neurons contribute to auditory processing in the TS. Here, we demonstrated that optogenetic manipulation of PV neuron activity significantly altered the auditory responses of SPNs, providing valuable insights into the role of the TS PV interneurons in auditory processing and their potential role in auditory-related behaviors.","PeriodicalId":22786,"journal":{"name":"The Journal of Neuroscience","volume":"48 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138592081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-07DOI: 10.1523/jneurosci.0356-23.2023
S. Weimann, Chao Zhang, R. M. Burger
The medial nucleus of the trapezoid body (MNTB) has been intensively investigated as a primary source of inhibition in brainstem auditory circuitry. MNTB-derived inhibition plays a critical role in the computation of sound location, as temporal features of sounds are precisely conveyed through the calyx of Held/MNTB synapse. In adult gerbils, cholinergic signaling influences sound-evoked responses of MNTB neurons via nicotinic acetylcholine receptors (nAChRs) (Zhang et al., 2021) establishing a modulatory role for cholinergic input to this nucleus. However, the cellular mechanisms through which acetylcholine (ACh) mediates this modulation in the MNTB remain obscure. To investigate these mechanisms, we used whole-cell current and voltage-clamp recordings to examine cholinergic physiology in MNTB neurons from Mongolian gerbils(Merionas unguiculatis)of both sexes. Membrane excitability was assessed in brain slices, in pre- (p9-13) and post-hearing onset (p18-20) MNTB neurons during bath application of agonists and antagonists of nicotinic (nAChRs) and muscarinic receptors (mAChRs). Muscarinic activation induced a potent increase in excitability most prominently prior to hearing onset with nAChR modulation emerging at later time points. Pharmacological manipulations further demonstrated that the voltage gated K+channel KCNQ (Kv7) is the downstream effector of mAChR activation that impacts excitability early in development. Cholinergic modulation of Kv7 reduces outward K+conductance and depolarizes resting membrane potential. Immunolabeling revealed expression of Kv7 channels as well as mAChRs containing M1 and M3 subunits. Together, our results suggest that mAChR modulation is prominent but transient in the developing MNTB and that cholinergic modulation functions to shape auditory circuit development.Significance statementThis study is the first to examine downstream cellular mechanisms that underlie modulatory effects of acetylcholine (ACh) in MNTB neurons. The MNTB is a primary source of inhibition in the superior olive and features the calyx of Held, an intensively studied giant synapse that plays a pivotal role in precise encoding of acoustic cues. Recently, we discovered that ACh modulates MNTB responses in adult gerbils through nicotinic receptors. Here, we demonstrate that ACh has potent effects on membrane excitability prior to hearing onset primarily via muscarinic receptors and describe the expression of two muscarinic receptor subtypes. Our results suggest that developmentally transient cholinergic modulation of a voltage-gated K+conductance is poised to influence circuit development during the peri-hearing onset period.
{"title":"A Developmental Switch in Cholinergic Mechanisms of Modulation in the Medial Nucleus of the Trapezoid Body","authors":"S. Weimann, Chao Zhang, R. M. Burger","doi":"10.1523/jneurosci.0356-23.2023","DOIUrl":"https://doi.org/10.1523/jneurosci.0356-23.2023","url":null,"abstract":"The medial nucleus of the trapezoid body (MNTB) has been intensively investigated as a primary source of inhibition in brainstem auditory circuitry. MNTB-derived inhibition plays a critical role in the computation of sound location, as temporal features of sounds are precisely conveyed through the calyx of Held/MNTB synapse. In adult gerbils, cholinergic signaling influences sound-evoked responses of MNTB neurons via nicotinic acetylcholine receptors (nAChRs) (Zhang et al., 2021) establishing a modulatory role for cholinergic input to this nucleus. However, the cellular mechanisms through which acetylcholine (ACh) mediates this modulation in the MNTB remain obscure. To investigate these mechanisms, we used whole-cell current and voltage-clamp recordings to examine cholinergic physiology in MNTB neurons from Mongolian gerbils(Merionas unguiculatis)of both sexes. Membrane excitability was assessed in brain slices, in pre- (p9-13) and post-hearing onset (p18-20) MNTB neurons during bath application of agonists and antagonists of nicotinic (nAChRs) and muscarinic receptors (mAChRs). Muscarinic activation induced a potent increase in excitability most prominently prior to hearing onset with nAChR modulation emerging at later time points. Pharmacological manipulations further demonstrated that the voltage gated K+channel KCNQ (Kv7) is the downstream effector of mAChR activation that impacts excitability early in development. Cholinergic modulation of Kv7 reduces outward K+conductance and depolarizes resting membrane potential. Immunolabeling revealed expression of Kv7 channels as well as mAChRs containing M1 and M3 subunits. Together, our results suggest that mAChR modulation is prominent but transient in the developing MNTB and that cholinergic modulation functions to shape auditory circuit development.Significance statementThis study is the first to examine downstream cellular mechanisms that underlie modulatory effects of acetylcholine (ACh) in MNTB neurons. The MNTB is a primary source of inhibition in the superior olive and features the calyx of Held, an intensively studied giant synapse that plays a pivotal role in precise encoding of acoustic cues. Recently, we discovered that ACh modulates MNTB responses in adult gerbils through nicotinic receptors. Here, we demonstrate that ACh has potent effects on membrane excitability prior to hearing onset primarily via muscarinic receptors and describe the expression of two muscarinic receptor subtypes. Our results suggest that developmentally transient cholinergic modulation of a voltage-gated K+conductance is poised to influence circuit development during the peri-hearing onset period.","PeriodicalId":22786,"journal":{"name":"The Journal of Neuroscience","volume":"36 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138593828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-07DOI: 10.1523/jneurosci.0877-23.2023
Karen M. Fisher, Joseph Garner, C. Darian‐Smith
Spinal cord injury (SCI) is devastating, with limited treatment options and variable outcomes. Mostin vivoSCI research has focused on the acute and early post-injury periods, and the promotion of axonal growth, so little is understood about the clinically stable chronic state, axonal growth over time, and what plasticity endures.Here, we followed animals into the chronic phase following SCI, to address this gap. Macaques received a targeted deafferentation, affecting three digits of one hand, and were divided into short (4-6 months) or long term (11-12 months) groups, based on post-injury survival times. Male monkeys were assessed behaviorally, where possible, and all exhibited an initial post-injury deficit in manual dexterity, with gradual functional recovery over two months.We previously reported extensive sprouting of somatosensory corticospinal (S1 CST) fibers in the dorsal horn in the first 5 post-injury months. Here we show that by 1 year, the S1 CST sprouting is pruned, with the terminal territory resembling control animals. This was reflected in the number of putatively ‘functional’ synapses observed, which increased over the first 4-5 months, and then returned to baseline by 1 year. Microglia density also increased in the affected dorsal horn at 4-6 months, and then decreased, but did not return to baseline by 1 year, suggesting refinement continues beyond this time.Overall, there is a long period of reorganization and consolidation of adaptive circuitry in the dorsal horn, extending well beyond the initial behavioral recovery. This provides a potential window to target therapeutic opportunities during the chronic phase.Significance statementMost preclinical studies of spinal cord injury focus on the early phases of recovery, during which the greatest behavioral improvements occur and there is significant sprouting of spared fibers. Here, we extended these observations into the chronic phase, in a primate model of spinal injury affecting hand function, to see if these changes were maintained long term. We show that following an early period of corticospinal (CST) and spared primary afferent sprouting, afferents remain stable while exuberant CST sprouts are pruned back to their baseline range. The presence and activation of microglia demonstrates that this process is driven partly by inflammation. Our findings provide important new insight into the chronic phase of recovery, and the potential for longer term plasticity.
{"title":"Chronic Adaptations in the Dorsal Horn following a cervical spinal cord injury in primates","authors":"Karen M. Fisher, Joseph Garner, C. Darian‐Smith","doi":"10.1523/jneurosci.0877-23.2023","DOIUrl":"https://doi.org/10.1523/jneurosci.0877-23.2023","url":null,"abstract":"Spinal cord injury (SCI) is devastating, with limited treatment options and variable outcomes. Mostin vivoSCI research has focused on the acute and early post-injury periods, and the promotion of axonal growth, so little is understood about the clinically stable chronic state, axonal growth over time, and what plasticity endures.Here, we followed animals into the chronic phase following SCI, to address this gap. Macaques received a targeted deafferentation, affecting three digits of one hand, and were divided into short (4-6 months) or long term (11-12 months) groups, based on post-injury survival times. Male monkeys were assessed behaviorally, where possible, and all exhibited an initial post-injury deficit in manual dexterity, with gradual functional recovery over two months.We previously reported extensive sprouting of somatosensory corticospinal (S1 CST) fibers in the dorsal horn in the first 5 post-injury months. Here we show that by 1 year, the S1 CST sprouting is pruned, with the terminal territory resembling control animals. This was reflected in the number of putatively ‘functional’ synapses observed, which increased over the first 4-5 months, and then returned to baseline by 1 year. Microglia density also increased in the affected dorsal horn at 4-6 months, and then decreased, but did not return to baseline by 1 year, suggesting refinement continues beyond this time.Overall, there is a long period of reorganization and consolidation of adaptive circuitry in the dorsal horn, extending well beyond the initial behavioral recovery. This provides a potential window to target therapeutic opportunities during the chronic phase.Significance statementMost preclinical studies of spinal cord injury focus on the early phases of recovery, during which the greatest behavioral improvements occur and there is significant sprouting of spared fibers. Here, we extended these observations into the chronic phase, in a primate model of spinal injury affecting hand function, to see if these changes were maintained long term. We show that following an early period of corticospinal (CST) and spared primary afferent sprouting, afferents remain stable while exuberant CST sprouts are pruned back to their baseline range. The presence and activation of microglia demonstrates that this process is driven partly by inflammation. Our findings provide important new insight into the chronic phase of recovery, and the potential for longer term plasticity.","PeriodicalId":22786,"journal":{"name":"The Journal of Neuroscience","volume":"55 30","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138593196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-07DOI: 10.1523/jneurosci.1206-23.2023
Franco Giarrocco, Vincent D Costa, Benjamin M. Basile, Maia S. Pujara, Elisabeth A. Murray, B. Averbeck
Deciding whether to forego immediate rewards or explore new opportunities is a key component of flexible behavior and is critical for the survival of the species. Although previous studies have shown that different cortical and subcortical areas, including the amygdala and ventral striatum (VS), are implicated in representing the immediate (exploitative) and future (explorative) value of choices, the effect of the motor system used to make choices has not been examined. Here we tested male rhesus macaques with amygdala or VS lesions on two versions of a three-arm bandit task where choices were registered with either a saccade or an arm movement. In both tasks we presented the monkeys with explore-exploit tradeoffs by periodically replacing familiar options with novel options that had unknown reward probabilities. We found that monkeys explored more with saccades but showed better learning with arm movements. VS lesions caused the monkeys to be more explorative with arm movements and less explorative with saccades, although this may have been due to an overall decrease in performance. VS lesions affected the monkeys’ ability to learn novel stimulus-reward associations in both tasks, while after amygdala lesions this effect was stronger when choices were made with saccades. Further, on average, VS and amygdala lesions reduced the monkeys’ ability to choose better options only when choices were made with a saccade. These results show that learning reward value associations to manage explore-exploit behaviors is motor-system dependent and they further define the contributions of amygdala and VS to reinforcement learning.Significance StatementThe amygdala and VS are known to be important for learning reward associations and for mediating explore-exploit behaviors. These behaviors are typically studied in experimental paradigms where choices are made with a single motor system. Here we show that nonhuman primates mediate explore-exploit behaviors in a motor system-dependent way. Monkeys were more explorative with eye movements but showed better learning performance with arm movements. Moreover, we showed different effects of amygdala and VS lesions on explore-exploit behaviors based on the motor system implementing task choices. Thus, we further define amygdala and VS contributions to explore-exploit behaviors and suggest that a different value representation might be driving learning in the oculomotor and skeletomotor systems.
{"title":"Motor system-dependent effects of amygdala and ventral striatum lesions on explore-exploit behaviors","authors":"Franco Giarrocco, Vincent D Costa, Benjamin M. Basile, Maia S. Pujara, Elisabeth A. Murray, B. Averbeck","doi":"10.1523/jneurosci.1206-23.2023","DOIUrl":"https://doi.org/10.1523/jneurosci.1206-23.2023","url":null,"abstract":"Deciding whether to forego immediate rewards or explore new opportunities is a key component of flexible behavior and is critical for the survival of the species. Although previous studies have shown that different cortical and subcortical areas, including the amygdala and ventral striatum (VS), are implicated in representing the immediate (exploitative) and future (explorative) value of choices, the effect of the motor system used to make choices has not been examined. Here we tested male rhesus macaques with amygdala or VS lesions on two versions of a three-arm bandit task where choices were registered with either a saccade or an arm movement. In both tasks we presented the monkeys with explore-exploit tradeoffs by periodically replacing familiar options with novel options that had unknown reward probabilities. We found that monkeys explored more with saccades but showed better learning with arm movements. VS lesions caused the monkeys to be more explorative with arm movements and less explorative with saccades, although this may have been due to an overall decrease in performance. VS lesions affected the monkeys’ ability to learn novel stimulus-reward associations in both tasks, while after amygdala lesions this effect was stronger when choices were made with saccades. Further, on average, VS and amygdala lesions reduced the monkeys’ ability to choose better options only when choices were made with a saccade. These results show that learning reward value associations to manage explore-exploit behaviors is motor-system dependent and they further define the contributions of amygdala and VS to reinforcement learning.Significance StatementThe amygdala and VS are known to be important for learning reward associations and for mediating explore-exploit behaviors. These behaviors are typically studied in experimental paradigms where choices are made with a single motor system. Here we show that nonhuman primates mediate explore-exploit behaviors in a motor system-dependent way. Monkeys were more explorative with eye movements but showed better learning performance with arm movements. Moreover, we showed different effects of amygdala and VS lesions on explore-exploit behaviors based on the motor system implementing task choices. Thus, we further define amygdala and VS contributions to explore-exploit behaviors and suggest that a different value representation might be driving learning in the oculomotor and skeletomotor systems.","PeriodicalId":22786,"journal":{"name":"The Journal of Neuroscience","volume":"26 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138591816","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-07DOI: 10.1523/jneurosci.0727-23.2023
David L. Bernstein, Stacia I. Lewandowski, Christina Besada, Delaney Place, Rodrigo A. España, O. Mortensen
The mesolimbic dopamine system is a crucial component of reward and reinforcement processing, including the psychotropic effects of drugs of abuse such as cocaine. Drugs of abuse can activate intracellular signaling cascades that engender long-term molecular changes to the brain reward circuitry, which can promote further drug use. However, gaps remain about how the activity of these signaling pathways, such as ERK1/2 signaling, can affect cocaine-induced neurochemical plasticity and cocaine-associated behaviors specifically within dopaminergic cells. To enable specific modulation of ERK1/2 signaling in dopaminergic neurons of the ventral tegmental area, we utilize a viral construct that Cre-dependently expresses Map kinase phosphatase 3 (MKP3) to reduce the activity of ERK1/2, in combination with transgenic rats that express Cre in tyrosine hydroxylase (TH)-positive cells. Following viral transfection, we found an increase in the surface expression of the dopamine transporter (DAT), a protein associated with dopamine signaling, dopamine transmission, and cocaine-associated behavior. We found that inactivation of ERK1/2 reduced posttranslational phosphorylation of the DAT, attenuated the ability of cocaine to inhibit the DAT, and decreased motivation for cocaine without affecting associative learning as tested by conditioned place preference. Together, these results indicate that ERK1/2 signaling plays a critical role in shaping the dopamine response to cocaine and may provide additional insights into the function of dopaminergic neurons. Further, these findings lay important groundwork towards the assessment of how signaling pathways and their downstream effectors influence dopamine transmission and could ultimately provide therapeutic targets for treating cocaine use disorders.Significance StatementDopamine signaling is critically involved in mediating cocaine-associated behaviors. Here we demonstrate a role for the ERK1/2 signaling pathway and its associated phosphatase, MKP3, specifically in dopamine neurons in regulating dopamine signaling in rats. Furthermore, we demonstrate that this modulation of the ERK1/2 signaling pathway affects cocaine associated behaviors, including the motivation for cocaine. This work could help identify downstream targets of the ERK1/2 signaling pathway that could be involved in the development of cocaine use disorders.
{"title":"Inactivation of ERK1/2 signaling in dopaminergic neurons by map kinase phosphatase MKP3 regulates dopamine signaling and motivation for cocaine","authors":"David L. Bernstein, Stacia I. Lewandowski, Christina Besada, Delaney Place, Rodrigo A. España, O. Mortensen","doi":"10.1523/jneurosci.0727-23.2023","DOIUrl":"https://doi.org/10.1523/jneurosci.0727-23.2023","url":null,"abstract":"The mesolimbic dopamine system is a crucial component of reward and reinforcement processing, including the psychotropic effects of drugs of abuse such as cocaine. Drugs of abuse can activate intracellular signaling cascades that engender long-term molecular changes to the brain reward circuitry, which can promote further drug use. However, gaps remain about how the activity of these signaling pathways, such as ERK1/2 signaling, can affect cocaine-induced neurochemical plasticity and cocaine-associated behaviors specifically within dopaminergic cells. To enable specific modulation of ERK1/2 signaling in dopaminergic neurons of the ventral tegmental area, we utilize a viral construct that Cre-dependently expresses Map kinase phosphatase 3 (MKP3) to reduce the activity of ERK1/2, in combination with transgenic rats that express Cre in tyrosine hydroxylase (TH)-positive cells. Following viral transfection, we found an increase in the surface expression of the dopamine transporter (DAT), a protein associated with dopamine signaling, dopamine transmission, and cocaine-associated behavior. We found that inactivation of ERK1/2 reduced posttranslational phosphorylation of the DAT, attenuated the ability of cocaine to inhibit the DAT, and decreased motivation for cocaine without affecting associative learning as tested by conditioned place preference. Together, these results indicate that ERK1/2 signaling plays a critical role in shaping the dopamine response to cocaine and may provide additional insights into the function of dopaminergic neurons. Further, these findings lay important groundwork towards the assessment of how signaling pathways and their downstream effectors influence dopamine transmission and could ultimately provide therapeutic targets for treating cocaine use disorders.Significance StatementDopamine signaling is critically involved in mediating cocaine-associated behaviors. Here we demonstrate a role for the ERK1/2 signaling pathway and its associated phosphatase, MKP3, specifically in dopamine neurons in regulating dopamine signaling in rats. Furthermore, we demonstrate that this modulation of the ERK1/2 signaling pathway affects cocaine associated behaviors, including the motivation for cocaine. This work could help identify downstream targets of the ERK1/2 signaling pathway that could be involved in the development of cocaine use disorders.","PeriodicalId":22786,"journal":{"name":"The Journal of Neuroscience","volume":"27 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138591217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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