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of the spatio-molecular organization defining four internal STN domains, and their separation from the PSTN a Left: Gross schematics of the STN and PSTN in dark and light gray representing the previously known distribution of Pitx2 and Vglut2 mRNAs which are both stronger in STN than PSTN. Right: snRNASeq and FISH data presented in present study now allow spatio-molecular distinction of the STN and PSTN based on molecular markers and anatomical positions. mRNA pattern analysis at three brain levels (S1-S3) shows how the anatomy of the STN and PSTN changes with anteroposterior levels, with the STN surrounded by PSTN at the S3 level. The data also allows further separation of the STN structure into four molecularly distinct internal domains: the STNa, STNb, STNc and STNds. Note that STNds represents a dorsal strip only present at the S1 and S2 levels. At S3 level, only STNa and PSTN detected. b Table shows representation of mRNAs detected in each STN domain (STNa, STNb, STNc and STNds) and in the PSTN by FISH analysis in mouse brain tissue; data also presented in Table 2. Note that co-localization with Pitx2 mRNA is presented with color coding: Black mRNA, Pitx2+; Blue mRNA, Pitx2+/Pitx2-mixed; Red mRNA, Pitx2-. Abbreviations: FISH, fluorescent in situ hybridization; STN, Subthalamic nucleus; PSTN, Parasubthalamic nucleus.
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The subthalamic nucleus (STN) is crucial for normal motor, limbic and associative function. STN dysregulation is correlated with several brain disorders, including Parkinsonʼs disease and obsessive compulsive disorder (OCD), for which high-frequency stimulation of the STN is increasing as therapy. However, clinical progress is hampered by poor know...
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... These observations highlight the need for further understanding of the anatomical features of STN, and how this nucleus connects within the brain. Apart from the complex anatomy of STN, a striking heterogeneity in its transcriptomic landscape was recently revealed by spatiomolecular data originated from single-nuclei RNA-sequencing (snRNASeq) in mice 67 . ...
... Notably, 5´HT1A and 5´HT2A receptors were not detected 94 . In mice, mRNA for 5´HT2C receptor was reported to be present along the entire STN structure, in a pattern similar to Vglut2 mRNA 67 . Dopamine: The STN receives sparse dopaminergic projections from the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) as reported in monkeys 95,96 and humans 73 . ...
... Novel gene expressions detected within the STN of rodents. Similar to the human STN, the rodent STN shares the biconvex morphology and distribution of some cellular markers, including the distribution of Parvalbumin localized at the dorsal aspect and Calbindin 2 towards the ventral aspect of the STN 33,36,52,67,73 . However, there are also striking differences between rodent and primate, discussed further below. ...
The subthalamic nucleus (STN) is a major neuromodulation target for the alleviation of neurological and neuropsychiatric symptoms using deep brain stimulation (DBS). STN-DBS is today applied as treatment in Parkinson´s disease, dystonia, essential tremor, and obsessive-compulsive disorder (OCD). STN-DBS also shows promise as a treatment for refractory Tourette syndrome. However, the internal organization of the STN has remained elusive and challenges researchers and clinicians: How can this small brain structure engage in the multitude of functions that renders it a key hub for therapeutic intervention of a variety of brain disorders ranging from motor to affective to cognitive? Based on recent gene expression studies of the STN, a comprehensive view of the anatomical and cellular organization, including revelations of spatio-molecular heterogeneity, is now possible to outline. In this review, we focus attention to the neurobiological architecture of the STN with specific emphasis on molecular patterns discovered within this complex brain area. Studies from human, non-human primate, and rodent brains now reveal anatomically defined distribution of specific molecular markers. Together their spatial patterns indicate a heterogeneous molecular architecture within the STN. Considering the translational capacity of targeting the STN in severe brain disorders, the addition of molecular profiling of the STN will allow for advancement in precision of clinical STN-based interventions.
... The subpopulation-specific synaptic organization we revealed might generalize to other synaptic inputs to the SNr, including the pallidonigral projection. We speculate that a consequence of this differential organization might be a differential vulnerability of synaptic inputs to the SNr in pathological conditions affecting basal ganglia functioning, including Alcohol Use Disorder and Parkinson's Disease 26,39,40 . ...
While cortico-striatal circuit deficits contribute to Alcohol Use Disorder, the impact of alcohol on synaptic function in the basal ganglia output, the substantia nigra pars reticulata (SNr), remains unclear. Here, we found that the inputs from the dorsomedial (DMS) and dorsolateral striatum (DLS) differ in their presynaptic properties and target molecularly distinct subpopulations of SNr neurons. We also discovered that indirect pathway subthalamic (STN) inputs to the medial and lateral SNr have different presynaptic properties and that STN inputs are stronger in the lateral SNr. Chronic alcohol exposure (CIE) potentiated DLS inputs but did not affect the strength and presynaptic release properties of DMS and subthalamic inputs to SNr neurons. Chemogenetic inhibition of DLS direct pathway projection neurons impaired action performance in an operant conditioning task in CIE mice but not control mice. Overall, our work identifies a synaptic mechanism whereby chronic alcohol induces a gain of function for action control in direct pathway neurons in the dorsolateral striatum.
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Chronic alcohol selectively potentiates DLS synaptic inputs to the SNr, enhancing their role in action control.
... As simplified models of the basal ganglia emphasize feedforward circuitry, intrinsic feedback circuits are often ignored. Importantly, although most circuit models assume a homogeneous neuronal population, recent studies argue that neuronal heterogeneity is common across the basal ganglia [2][3][4][5][6][7][8][9][10] . ...
... Three independent studies have convincingly demonstrated that STN inputs target PV + neurons more strongly than NPAS1 + neurons 13,15,39 . While the neuronal makeup of the STN was generally thought to be homo geneous, recent studies show that STN neurons are more heterogeneous than previously expected 6,9,58,[62][63][64] . Therefore, it will be important to determine whether PV + -targeting neurons within the STN are distinct from those targeting NPAS1 + neurons. ...
The external globus pallidus (GPe) of the basal ganglia has been underappreciated owing to poor understanding of its cells and circuits. It was assumed that the GPe consisted of a homogeneous neuron population primarily serving as a 'relay station' for information flowing through the indirect basal ganglia pathway. However, the advent of advanced tools in rodent models has sparked a resurgence in interest in the GPe. Here, we review recent data that have unveiled the cell and circuit complexity of the GPe. These discoveries have revealed that the GPe does not conform to traditional views of the basal ganglia. In particular, recent evidence confirms that the afferent and efferent connections of the GPe span both the direct and the indirect pathways. Furthermore, the GPe displays broad interconnectivity beyond the basal ganglia, consistent with its emerging multifaceted roles in both motor and non-motor functions. In summary, recent data prompt new proposals for computational rules of the basal ganglia.
... However, in modern literature, brain structures/regions have also been defined using other important organizational features such as connectional patterns (Fudge et al., 2004;Gehrlach et al., 2020) and molecular signatures (Wallén-Mackenzie et al., 2020;Chen et al., 2022;Ding et al., 2022) as well as using combination of multimodal data van Hoesen, 2010, 2015;Ding, 2022). In this study, we aim to investigate the connections of the region located immediately lateral to A30 in rat and mouse brains to determine whether this region possess similar connectional patterns as the monkey PCC (mainly A23) does. ...
Posterior cingulate cortex (area 23, A23) in human and monkeys is a critical component of the default mode network and is involved in many diseases such as Alzheimer’s disease, autism, depression, attention deficit hyperactivity disorder and schizophrenia. However, A23 has not yet identified in rodents, and this makes modeling related circuits and diseases in rodents very difficult. Using a comparative approach, molecular markers and unique connectional patterns this study has uncovered the location and extent of possible rodent equivalent (A23~) of the primate A23. A23 ~ but not adjoining areas in the rodents displays strong reciprocal connections with anteromedial thalamic nucleus. Rodent A23 ~ reciprocally connects with the medial pulvinar and claustrum as well as with anterior cingulate, granular retrosplenial, medial orbitofrontal, postrhinal, and visual and auditory association cortices. Rodent A23 ~ projects to dorsal striatum, ventral lateral geniculate nucleus, zona incerta, pretectal nucleus, superior colliculus, periaqueductal gray, and brainstem. All these findings support the versatility of A23 in the integration and modulation of multimodal sensory information underlying spatial processing, episodic memory, self-reflection, attention, value assessment and many adaptive behaviors. Additionally, this study also suggests that the rodents could be used to model monkey and human A23 in future structural, functional, pathological, and neuromodulation studies.
... Researchers have implemented single-nuclei RNA sequencing of the mouse PSTN followed by histological analysis of 19 candidate genes 22 . As a result, Calb2 (calretinin, CR) mRNA was found at high levels throughout the PSTN 22 . ...
... Researchers have implemented single-nuclei RNA sequencing of the mouse PSTN followed by histological analysis of 19 candidate genes 22 . As a result, Calb2 (calretinin, CR) mRNA was found at high levels throughout the PSTN 22 . Here, we used fiber photometry to investigate the activity of PSTN CR neurons during the spontaneous sleep-wake cycle and behavior. ...
The parasubthalamic nucleus (PSTN) is considered to be involved in motivation, feeding and hunting, all of which are highly depending on wakefulness. However, the roles and underlying neural circuits of the PSTN in wakefulness remain unclear. Neurons expressing calretinin (CR) account for the majority of PSTN neurons. In this study in male mice, fiber photometry recordings showed that the activity of PSTNCR neurons increased at the transitions from non-rapid eye movement (non-REM, NREM) sleep to either wakefulness or REM sleep, as well as exploratory behavior. Chemogenetic and optogenetic experiments demonstrated that PSTNCR neurons were necessary for initiating and/or maintaining arousal associated with exploration. Photoactivation of projections of PSTNCR neurons revealed that they regulated exploration-related wakefulness by innervating the ventral tegmental area. Collectively, our findings indicate that PSTNCR circuitry is essential for the induction and maintenance of the awake state associated with exploration.
... To address the functional difference between the STN-SNr and STN-GPi projections, we compared their synaptic transmission with optogenetics and brain slice patch-clamp recordings. Considering that glutamatergic neurons are the principal neurons (>95%) in the STN in rodents, 1,2,21,34,35 we intracranially injected AAV-CaMKII-ChR2-eYFP into the STN to specifically label STN glutamatergic neurons ( Figures 1A-1C) 21,23 and this procedure allows for photostimulation of STN neurons (Figures S1A-S1C) and visualization of STN glutamatergic axonal fibers and puncta in both the SNr ( Figure S1D) and GPi ( Figure S1E). Using the brain slice patch-clamp technique ( Figure 1D), we confirmed that ChR2-labeled STN neurons responded to blue light stimuli with inward currents (photo-currents) at a holding potential of À70 mV ( Figure S1B). ...
The subthalamic nucleus (STN) controls basal ganglia outputs via the substantia nigra pars reticulata (SNr) and the globus pallidus internus (GPi). However, the synaptic properties of these projections and their roles in motor control remain unclear. We show that the STN-SNr and STN-GPi projections differ markedly in magnitude and activity-dependent plasticity despite the existence of collateral STN neurons projecting to both the SNr and GPi. Stimulation of either STN projection reduces locomotion; in contrast, inhibition of either the STN-SNr projection or collateral STN neurons facilitates locomotion. In 6-OHDA-hemiparkinsonian mice, the STN-SNr projection is dramatically attenuated, but the STN-GPi projection is robustly enhanced; apomorphine inhibition of the STN-GPi projection through D2 receptors is significantly augmented and improves locomotion. Optogenetic inhibition of either the STN-SNr or STN-GPi projection improves parkinsonian bradykinesia. These results suggest that the STN-GPi and STN-SNr projections are differentially involved in motor control in physiological and parkinsonian conditions.
... Interestingly, Péron et al. (2013) also proposed a model stating that the STN produces a neural co-activation, temporally organized, in both cortical and subcortical levels, which is necessary to generate emotions and related feelings. Alternatively, this similar behavioral result of opposite optogenetic manipulations of the STN would rely on a more complex internal organization of this structure than what is known today (see for instance Wallén-Mackenzie et al., 2020). Further studies are necessary to elucidate this anatomical-functional organization of the STN, and its complex roles in behavior. ...
Human social behavior is a complex construct requiring a wide range of cognitive abilities and is critically impaired in numerous neuropsychiatric diseases. Living in complex social groups, rodents offer suitable models to elucidate neural processing of social cognition. Recently, a potential involvement of the subthalamic nucleus (STN) in rats social behavior has been pointed out. For example, we showed that STN lesions abolish the modulatory effect of the familiarity on the rewarding value of social stimuli, questioning the involvement of STN in peer recognition. In this study, we thus assess the effects of STN lesions and optogenetic manipulations on peer and object recognition. STN optogenetic inhibition, like lesions, impair social recognition memory, while STN optogenetic high-frequency (HF) stimulation leads to a specific alteration of social encoding memory. None of these manipulations seem to interfere with social investigation, objects recognition memory, nor social novelty preference. Finally, STN optogenetic inhibition, but neither HF-stimulation, nor lesions, leads to an alteration of the cage-mate recognition memory. Overall, these results show that physiological activity of STN is necessary for rats to show a proper social recognition memory performance and question the possible detrimental effects of STN deep brain stimulation on these processes in human patients
... Significant induction of c-Fos expression, a marker of neuronal activation, has been observed in the rodent PSTN following predatory hunting of cockroaches, early active phase surge of food intake, refeeding after food deprivation, anorexia-inducing amino-acid deficient diet refeeding, and sucrose drinking following water deprivation (8)(9)(10)(11)(12)(13)(14). While all PSTN neurons are glutamatergic (VGluT2-positive), they comprise subpopulations expressing high levels of either Tac1 (encoding preprotackykinin-A, a precursor of substance P and neurokinin A) or Crh (encoding corticotropin-releasing factor, CRF) with minimal overlap (14)(15)(16). Both PSTN Tac1 and PSTN Crh neurons show strong activation in response to refeeding in food-deprived mice (14). ...
The parasubthalamic nucleus (PSTN) is responsive to refeeding after food deprivation and PSTN subpopulations can suppress feeding. However, no study directly addressed the role of PSTN neurons activated upon food access resumption. Here we show that the ensemble of refeeding-activated PSTN neurons massively increases the latency to initiate refeeding with both familiar and novel food but exerts limited control over the amount of food consumed by hungry mice. This ensemble also delays sucrose consumption but accelerates water consumption in thirsty mice. We next sought to identify which subpopulations of PSTN neurons might be driving these effects. We discovered that PSTN Tac1 neurons projecting to the CeA selectively suppress feeding initiation while PSTN Crh neurons surprisingly promote the consumption of novel, palatable substances. Our results demonstrate the key role of endogenous PSTN activity in the control of feeding initiation and identify PSTN subpopulations counteracting each others influence on consummatory behaviors.
... PACAP is well characterized in aversive behaviors and feeding behaviors 28,30,43 . Consistent with a previous report 44 , we found that PACAP is highly enriched in the PSTN (Fig. 6a). A recent paper demonstrated two discrete PSTN subpopulations, those that Article https://doi.org/10.1038/s41467-022-35634-2 ...
Feeding behavior is adaptively regulated by external and internal environment, such that feeding is suppressed when animals experience pain, sickness, or fear. While the lateral parabrachial nucleus (lPB) plays key roles in nociception and stress, neuronal pathways involved in feeding suppression induced by fear are not fully explored. Here, we investigate the parasubthalamic nucleus (PSTN), located in the lateral hypothalamus and critically involved in feeding behaviors, as a target of lPB projection neurons. Optogenetic activation of lPB-PSTN terminals in male mice promote avoidance behaviors, aversive learning, and suppressed feeding. Inactivation of the PSTN and lPB-PSTN pathway reduces fear-induced feeding suppression. Activation of PSTN neurons expressing pituitary adenylate cyclase-activating polypeptide (PACAP), a neuropeptide enriched in the PSTN, is sufficient for inducing avoidance behaviors and feeding suppression. Blockade of PACAP receptors impaires aversive learning induced by lPB-PSTN photomanipulation. These findings indicate that lPB-PSTN pathway plays a pivotal role in fear-induced feeding suppression.
... APOE and CLU have been previously associated with AD progress [25][26][27] (Fig. 4D). In the case of STXBP2, only a few studies have found its expression in the brain 28,29 however, there is no literature data reporting its association with AD. Our study uncovers its potential involvement in AD. ...
Spatially resolved proteomics is an emerging approach for mapping proteome heterogeneity of biological samples, however, it remains technically challenging due to the complexity of the tissue microsampling techniques and mass spectrometry analysis of nanoscale specimen volumes. Here, we describe a spatially resolved proteomics method based on the combination of tissue expansion with mass spectrometry-based proteomics, which we call Expansion Proteomics (ProteomEx). ProteomEx enables quantitative profiling of the spatial variability of the proteome in mammalian tissues at ~160 µm lateral resolution, equivalent to the tissue volume of 0.61 nL, using manual microsampling without the need for custom or special equipment. We validated and demonstrated the utility of ProteomEx for streamlined large-scale proteomics profiling of biological tissues including brain, liver, and breast cancer. We further applied ProteomEx for identifying proteins associated with Alzheimer’s disease in a mouse model by comparative proteomic analysis of brain subregions.
