Journal of Neuroscience最新文献

{"title":"Uncertainty, not mental content, drives dorsomedial prefrontal engagement during inferences about others.","authors":"Dilara Berkay,Adrianna C Jenkins","doi":"10.1523/jneurosci.1920-23.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.1920-23.2025","url":null,"abstract":"To navigate social life, humans make inferences about the intentions, beliefs, emotions, and personalities of other people, i.e., they mentalize. A network of brain regions consistently engages more during mentalizing than during carefully controlled comparison tasks, sometimes cited as evidence of domain-specific mentalizing processes. Here we investigated the possibility that engagement of these regions during mentalizing may be due to uncertainty. We scanned 46 participants (33 female, 13 male) using fMRI as they made mental and non-mental inferences (about human minds, human bodies, and physical objects) under varying levels of uncertainty. Uncertainty explained activation in a key region of the mentalizing network: the dorsal medial prefrontal cortex (DMPFC). Higher uncertainty was associated with greater DMPFC engagement across conditions, and, when controlling for uncertainty, DMPFC engagement did not differentiate mental from non-mental inferences. Results suggest that the apparently selective DMPFC engagement during social inference may be better understood as a response to uncertainty, which is often elevated in social contexts, with implications for the cognitive architecture of the social brain and disorders of social function.Significance statement Human social behavior often hinges on inferences about minds of other people (mentalizing), as highlighted by cases of atypical mentalizing, including autism. Longstanding debate surrounds whether mentalizing arises from specialized cognitive processes or more general mechanisms. In past research, the brain's \"mentalizing network\" is consistently more engaged during mentalizing than other activities, possibly supporting domain-specificity. In contrast, here we show that the engagement of a key brain region in the mentalizing network, the dorsal medial prefrontal cortex, can be explained as a response to uncertainty rather than mental content. This suggests a revision of scientific understanding of social cognition's neural basis, with possible implications for the origins of atypicalities in social behavior. .","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"35 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143893298","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":"Differential impact of retinal lesions on visual responses of LGN X and Y cells.","authors":"Jingyi Yang,Krystel Huxlin,Farran Briggs","doi":"10.1523/jneurosci.0436-25.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.0436-25.2025","url":null,"abstract":"Damage to retinal cells from disease or injury causes vision loss and remodeling of downstream visual information processing circuits. As retinal cell replacement therapies and prosthetics become increasingly viable, we must understand post-retinal consequences of retinal cell loss to optimally recover visual perception. Here, we asked whether loss of retinal ganglion cells (RGCs) differentially impacts postsynaptic neurons in the visual thalamus - the dorsal lateral geniculate nucleus (LGN) - of ferrets, highly visual carnivores. We hypothesized that RGC loss might impact X more than Y LGN neurons, as there is less divergence in X retinogeniculate connections. We induced excitotoxic lesions of RGCs in a single eye and recorded neurophysiological responses of both contra- and ipsi-lesional LGN neurons to a variety of visual stimuli. We observed loss of responses among many LGN neurons, presumably with receptive fields within the scotoma. We also observed contralesional LGN neurons with receptive fields within or at the border of the scotoma that responded consistently to drifting sinusoidal gratings and spatiotemporally dynamic stimuli, enabling their classification as X or Y cells. Contralesional Y cell responses remained intact while contralesional X cells demonstrated higher firing rates, altered tuning to stimulus contrast and temporal frequency, and reduced spike timing precision. Consistent with neurophysiological results, alpha RGCs appeared relatively spared compared to beta RGCs. Together, our findings show that retinal cell loss differentially impacts downstream neuronal circuits, suggesting that supplemental vision recovery therapies may need to target visual circuits specialized for acuity vision.Significance Statement Vision loss from damage to retinal neurons may be partially ameliorated by improving cell replacement therapies and retinal prosthetics. However, retinal cell loss likely causes remodeling of circuits downstream, e.g., in the visual thalamus, which may also require treatment to restore natural visual perception. We studied neurophysiological changes in the visual thalamus, immediately postsynaptic to retina, following excitotoxic lesions of retinal output neurons. We discovered disproportionate effects on thalamic cell types, whereby cells receiving divergent retinal inputs were spared and those with few-to-one inputs had altered, noisier responses. Our findings suggest that supplemental vision therapies may need to target specific visual pathways to optimize acuity vision.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"35 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143893227","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":"The Role of Neprilysin and Insulin-Degrading Enzyme in the Etiology of Sporadic Alzheimer's Disease.","authors":"Takahiro Morito,Shoko Hashimoto,Risa Takamura,Naoto Watamura,Naomasa Kakiya,Ryo Fujioka,Naomi Mihara,Misaki Sekiguchi,Kaori Watanabe-Iwata,Naoko Kamano,Mohan Qi,Yukio Matsuba,Satoshi Tsubuki,Takashi Saito,Nobuhisa Iwata,Hiroki Sasaguri,Takaomi C Saido","doi":"10.1523/jneurosci.2152-24.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.2152-24.2025","url":null,"abstract":"An age-dependent decline in the amyloid-β (Aβ)-degrading enzyme neprilysin (NEP) has been implicated in the pathogenesis of sporadic Alzheimer's disease (AD). Recently identified risk alleles in the NEP-coding gene further support its role in AD etiology. However, evidence for the impact of NEP on the pathophysiological progression of Aβ plaque formation, particularly in comparison to another Aβ-degrading enzyme, insulin-degrading enzyme (IDE), is still lacking. Furthermore, the functional impact of the NEP mutation, M8V, caused by the AD risk allele in the NEP gene, remains unexplored. Here we found that NEP deficiency in App NL-F mice accelerates Aβ plaque formation more prominently than IDE deficiency in both male and female mice. Additionally, NEP/IDE double knockout further exacerbated the plaque deposition of App NL-F mice, demonstrating a synergistic effect between the two enzymes. We also revealed that the M8V mutation in NEP reduced extracellular Aβ degradation in SH-SY5Y neuroblastoma cells, not by impairing catalytic activity but by increasing phosphorylation at an intracellular serine residue. This alteration in phosphorylation decreases NEP localization on the cell surface and extracellular vesicles, thereby limiting extracellular Aβ degradation. These observations point to the role of aging-associated neprilysin decline in sporadic AD pathogenesis and endorse the strategy of upregulating neprilysin activity to treat preclinical AD.Significance Statement Neprilysin (NEP) is a key amyloid-β (Aβ)-degrading enzyme in the brain, but its role in the pathophysiological progression of Aβ plaque formation remains controversial, particularly in comparison to another Aβ-degrading enzyme, insulin-degrading enzyme (IDE). Here, we show that NEP deficiency in App NL-F mice accelerates Aβ plaque formation more prominently than IDE deficiency. This effect is further exacerbated in NEP/IDE double knockout mice, demonstrating a synergistic relationship between the two enzymes. Moreover, the AD-associated NEP M8V mutation reduces extracellular Aβ degradation in neuroblastoma cells. These observations point to the role of aging-associated neprilysin decline in SAD pathogenesis and endorse the strategy of upregulating neprilysin activity to treat preclinical AD.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"10 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143893231","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":"Neural and behavioral correlates of individual variability in rat helping behavior: a role for social affiliation and oxytocin receptors.","authors":"R Hazani,J M Breton,E Trachtenberg,K Ruzal,B Shvalbo,B Kantor,A Maman,E Bigelman,S Cole,A Weller,I Ben-Ami Bartal","doi":"10.1523/jneurosci.0845-24.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.0845-24.2025","url":null,"abstract":"A prosocial response to others in distress is increasingly recognized as a natural behavior for many social species. While prosocial behavior is more frequently observed towards familiar conspecifics, even within the same social context, some individuals are more prone to help than others. In a rat helping behavior test where animals can release a distressed conspecific trapped inside a restrainer, most rats are motivated and consistently release the trapped rat ('openers'), yet around 30% do not open the restrainer ('non-openers'). To characterize the difference between these populations, behavioral and neural markers were compared between opener and non-opener rats in males and females. Openers showed significantly more social affiliative behavior both before and after door-opening compared to non-openers. Oxytocin receptor mRNA levels were higher in the nucleus accumbens (NAc), but not the anterior insula, of openers. Several transcription control pathways were significantly upregulated in openers' NAc. Chemogenetically inhibiting paraventricular oxytocin neurons did not significantly impair helping, but did reduce sociality measures, indicating that helping does not rely solely on oxytocin signaling. Analysis of brain-wide neural activity based on the immediate-early gene c-Fos in males revealed increased activity in openers in prosocial brain regions compared to non-openers. These include regions associated with empathy in humans (insula, somatosensory, cingulate and frontal cortices), and motivation and reward regions such as the NAc. These findings indicate that prosocial behavior may be predicted by affiliative behavior and activity in the prosocial neural network and provide targets for the investigation of causal mechanisms underlying prosocial behavior.Significance Statement Prosocial behavior is observed in many social species, including rodents, yet the determinants underlying why some animals help and others do not is poorly understood. Here, we show behavioral and neural differences between prosocial and non-prosocial pairs in a rat helping behavior test, with increased social interaction and nucleus accumbens oxytocin receptor gene expression in animals that helped.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"19 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143889291","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":"Heterogeneous effects of cognitive arousal on the contrast response in human visual cortex.","authors":"Jasmine Pan,Louis N Vinke,Joseph T McGuire,Sam Ling","doi":"10.1523/jneurosci.0798-24.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.0798-24.2025","url":null,"abstract":"While animal studies have found that arousal states modulate visual responses, direct evidence for effects of arousal on human vision remains limited. Here, we used fMRI to examine effects of cognitive arousal on the gain of contrast response functions (CRFs) in human visual cortex. To measure CRFs, we measured BOLD responses in early visual cortex (V1-V3) while participants (n=20, 14 females and 6 males) viewed stimuli that parametrically varied in contrast. To induce different cognitive arousal states, participants solved auditory arithmetic problems categorized as either Easy (low arousal) or Hard (high arousal). We found surprising diversity in the modulatory effects across individuals: some individuals exhibited enhanced neural response with increased arousal, whereas others exhibited the opposite effect - a decrease in response with increased arousal. The pattern of overall BOLD modulation showed within-individual stability and was correlated with the degree of arousal-driven change in pupil size. Individuals who exhibited larger increases in pupil size with the arousal manipulation tended to show greater arousal-related decreases in visuocortical responses. We speculate that the polarity of the modulatory effect by cognitive arousal may relate to individual differences in cognitive effort expended in the high-difficulty condition, with individuals reaching different points on an underlying non-monotonic function.Significance Statement While animal work suggests that arousal state has a profound impact on visual processing, the effects on human vision remain less understood. Here we assessed the influence of cognitive arousal on the neural gain of visual responses in humans to better characterize the mechanisms by which arousal affects vision. Minimal modulation was observed at the group level, but closer examination revealed substantial variability in modulation across individuals, with some showing enhancement and others exhibiting a decrease in neural modulation of visual responses with high arousal. Changes in pupil size correlated with neural modulation, suggesting a non-linear inverted-U relationship between cognitive arousal and visual processing. These results provide evidence of arousal's differential impact on vision across individuals.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"10 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143885272","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":"The role of the Ca2+-activated Cl- conductance in the membrane potential and light response of mouse rods.","authors":"Rikard Frederiksen,Paul J Bonezzi,Gordon L Fain,Alapakkam P Sampath","doi":"10.1523/jneurosci.1920-24.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.1920-24.2025","url":null,"abstract":"To characterize the function of the Ca2+-activated Cl- current ICl(Ca) in mammalian rod photoreceptors, we made patch-clamp recordings from retinal slices of mice (Mus musculus) of both sexes that lack Ano2 (TMEM16B). Depolarizing voltage ramps in solutions blocking K+ currents elicited a large outward current inhibited by the Cl-- channel blocker niflumic acid; this current was absent in Ano2-/- rods. The membrane potential of Ano2-/- rods was 10 - 15 mV more depolarized in darkness than WT or Cx36-/- rods, indicating a substantial resting Cl- permeability. Rod outer segment photocurrents were similar in waveform and amplitude in Ano2-/- and Cx36-/- rods, but photovoltages in Ano2-/- rods were nearly doubled. Measurements of light-response reversal potentials in rods with and without Ano2 suggest that the outer-segment conductance is nearly linear with a reversal potential of -9 mV; and that [Formula: see text] increases during the light response. Using these results, we estimated ECl from permeabilized-patch recordings of reversal potentials of Cx36-/- rods to have a mean value of -35 mV near the rod resting potential, but other evidence suggests that ECl may be more positive by as much as 10 - 15 mV. Thus activation of ICl(Ca) during the light response would be depolarizing. At dim intensities, the photocurrents of downstream rod bipolar cells were larger and about twice as sensitive in Ano2-/- retinas with reduced nonlinearity. These experiments show that Ca2+-activated Cl- currents in mammalian rods have more important roles in photoreceptor physiology than previously appreciated.Significance Statement To characterize the function of the Ca2+-activated Cl- channel in mammalian rods, we recorded from Ano2-/- mice with a disrupted channel gene. We show that these Cl- channels make a surprisingly large contribution to the rod resting permeability. Moreover, measurements of reversal potentials indicate that light produces an increase in Cl- conductance, which can only occur if the Ca2+ concentration near the channels is increasing even as the rod membrane potential is hyperpolarizing. We describe a novel method to make the first measurement of ECl in a mammalian rod, which is near to or somewhat positive of Erest Thus, channel activation would depolarize the rod. Ca2+-activated Cl- channels have more important roles in mammalian photoreceptor physiology than previously appreciated.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"24 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143885460","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":"A Novel APP Knock-In Mouse Model to Study the Protective Effects of the Icelandic Mutation In Vivo.","authors":"Maria Luisa Valle","doi":"10.1523/jneurosci.0164-25.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.0164-25.2025","url":null,"abstract":"","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"7 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872100","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":"The circadian clock component REV-ERBs is an analgesic target for cancer-induced tactile pain hypersensitivity.","authors":"Sai Yasukochi,Wakaba Yamakawa,Marie Taniguchi,Sayaka Itoyama,Akito Tsuruta,Naoki Kusunose,Tomoaki Yamauchi,Risako Nakamura,Naoya Matsunaga,Shigehiro Ohdo,Satoru Koyanagi","doi":"10.1523/jneurosci.1969-24.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.1969-24.2025","url":null,"abstract":"Neuropathic pain is one of the most intractable pain conditions associated with tumor growth compressing and damaging nerves. A troublesome hallmark symptom of neuropathic pain is hypersensitivity to innocuous stimuli, known as \"tactile allodynia,\" which is often refractory to currently available analgesics. Diurnal variations in pain hypersensitivity are common in patients with cancer, but the underlying mechanisms are enigmatic. Herein, we report that spinal expression of lipocalin-2 (LCN2) enhances pain sensitivity of NCTC2472 fibrosarcoma-implanted male mice during specific stages of the diurnal cycle. As the tumor grew, interleukin-6 (IL-6) levels increased in the spinal cord of the mice. Increased IL-6 levels stimulated LCN2 expression in spinal microglia, but this expression was periodically repressed by the circadian clock components REV-ERBα and REV-ERBβ. Notably, intra-spinal dorsal horn injection of lentiviral vectors expressing REV-ERBα or REV-ERBβ in tumor-bearing mice alleviated tactile allodynia. Furthermore, intrathecal injection of SR9009, a synthetic agonist of REV-ERBs, also attenuated cancer-induced pain hypersensitivity, accompanied by suppressing spinal LCN2 expression. These results suggest that temporal elevation of LCN2 expression decreases the threshold of tactile pain hypersensitivity induced by tumor growth. We propose that the circadian clock component of REV-ERBs is an effective target for alleviation of cancer-induced tactile allodynia, identifying a new class of analgesic agents.Significance statement Spinal expression of lipocalin-2 (LCN2) enhances pain sensitivity of NCTC2472 fibrosarcoma-implanted mice during specific stages of the diurnal cycle. Following tumor growth, an increase in interleukin-6 (IL-6) levels within spinal cord induces the microglial expression of LCN2, which is periodically suppressed by the circadian clock components REV-ERBα and REV-ERBβ. The temporal elevation of LCN2 expression decreases the threshold of tactile allodynia induced by tumor growth. Enhanced expression of REV-ERBs in spinal microglial and their pharmacological activation by the synthetic agonist SR9009 alleviate cancer-induced pain hypersensitivity. These findings reveal the circadian machinery affecting cancer-associated intractable pain and propose that REV-ERBs are an effective target for alleviation of cancer-associated neuropathic pain.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"1 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872095","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":"The anterior insula processes a time-resolved subjective risk prediction error.","authors":"Jae-Chang Kim,Lydia Hellrung,Stephan Nebe,Philippe N Tobler","doi":"10.1523/jneurosci.2302-24.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.2302-24.2025","url":null,"abstract":"The insula processes errors in the prediction of risky, motivationally relevant outcomes, and thereby is thought to respond similarly to better than predicted and worse than predicted outcomes. However, the nature of the encoded risk prediction error signals remained unclear. Moreover, the insula was proposed to preferentially process events and stimuli in the aversive domain, rather than in a domain-general fashion. Here we aimed to illuminate these issues. Within a Pavlovian task, participants (n=41; 19 women) rated both cues and outcomes, allowing us to quantify not only objective but also trial-specific subjective risk prediction errors. We found preferential coding of subjective risk prediction errors in the anterior insula and adjacent frontal cortex. This contrasted with preferential coding of objective risk prediction errors in the mid-insula. The anterior insula encoded the subjective risk prediction errors not only at the time of outcomes, but also at the time of cues, in-line with a temporally fine-grained computation of these prediction errors. Cue-induced subjective risk prediction error signals occurred predominantly in the aversive domain, while outcome-induced subjective risk prediction error signals occurred also in the appetitive domain. Domain-specific analyses of risk prediction errors elicited by the preceding outcome at the time of the next cue indicated that the anterior insula updates risk predictions more strongly in the aversive than the appetitive domain. Together, our findings specify the nature of risk prediction errors processed by the anterior insula as subjective, time-resolved, and partly domain-general (outcome), partly domain-preferential (cue), thereby reconciling apparently disparate lines of research.Significant Statement The anterior insula is a hub of the salience network, thought to process both good and bad surprises. However, salience needs defining and the nature of salience signals in anterior insula remained unclear. Here, we define salience as risk and use a Pavlovian task with subjectively evaluated cues and liquid outcomes, allowing us to determine unsigned surprise, i.e., risk prediction errors, at both time points. In a double dissociation, subjective risk prediction error signals occurred preferentially in anterior insula and objective signals in mid-insula. We also show that subjective risk prediction errors are preferentially encoded for aversive rather than appetitive cues. These findings unify divergent frameworks of insula function, specifying the insula's nuanced role in salience processing for motivated behavior.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"8 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872020","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":"Infralimbic projections to the substantia innominata-ventral pallidum constrain defensive behavior during extinction learning.","authors":"Carolina Fernandes-Henriques,Yuval Guetta,Mia Sclar,Rebecca Zhang,Yuka Miura,Katherine R Surrence,Allyson K Friedman,Ekaterina Likhtik","doi":"10.1523/jneurosci.1001-24.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.1001-24.2025","url":null,"abstract":"Fear extinction is critical for decreasing fear responses to a stimulus that no longer poses a threat. While it is known that the infralimbic region (IL) of the medial prefrontal cortex mediates retrieval of an extinction memory through projections to the basolateral amygdala (BLA), IL pathways contributing to extinction learning are not well-understood. Given the dense projection from the IL to the substantia innominata-ventral pallidum (SI/VP), an area that processes aversive and appetitive cues, we compared how the IL-SI/VP functions in extinction compared to the IL-BLA pathway in male mice. Using retrograde tracing, we demonstrate that IL projections to the SI/VP originate from superficial (L2/3) and deep cortical layers (L5), and that they are denser than IL projections to the BLA. Next, combining retrograde tracing with labeling for the immediate early gene cFos, we show increased activity of L5 IL-SI/VP output during extinction learning and increased activity of L2/3 IL-BLA output during extinction retrieval. Then, using in vitro recordings, we demonstrate that neurons in the IL-SI/VP pathway are more excitable during extinction learning than retrieval. Finally, using optogenetics we inactivate the IL-SI/VP pathway, and show that this increases defensive freezing during extinction learning and re-extinction, without affecting memory. Taken together, we demonstrate that the IL-SI/VP pathway is active during extinction learning, when it constrains the defensive freezing response. We propose that the IL acts as a switchboard operator, increasing IL L5 communication with the SI/VP during extinction learning, and IL L2/3 communication with the BLA during extinction retrieval.Significance Statement Fear extinction is a widely used behavioral approach to decrease conditioned fear, and projections from the infralimbic cortex to the amygdala are known to mediate extinction memory retrieval. However, less is known about the role of infralimbic pathways in extinction learning. We use neuroanatomical tracing, behavior, slice recordings, and circuit manipulation to show that infralimbic output to the substantia innominata-ventral pallidum, a region that processes aversive and appetitive stimuli, is denser than to the amygdala, and is more active during extinction learning than retrieval, when it acts to constrain the defensive freezing response. Thus, we posit that during extinction the infralimbic uses several lines of communication, one with the substantia innominata-ventral pallidum during learning one with the amygdala during retrieval.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"7 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866390","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}