Biology subjects

Meletis, K.

Publications and source records attributed to Meletis, K..

16 recordsLinked to original sources

bioRxiv2025

Selective innervation of subpopulations of striatal neurons by distinct sets of neurons of the external globus pallidus

The striatum, the primary input nucleus of the basal ganglia, contains diverse populations of projection neurons and interneurons, each with distinct roles in motor processing. The external globus pallidus contains distinct populations of inhibitory neurons that are highly interconnected with other regions of the basal ganglia. How pallidal neurons innervate different populations of striatal neurons is critical for our understanding of their role in motor processing. Here we use monosynaptic viral tracing in transgenic mice to quantitively define the organization of pallidostriatal connectivity. We show that FoxP2-expressing arkypallidal neurons provide the greatest input to the striatum, primarily targeting indirect pathway spiny projection neurons and cholinergic interneurons. In contrast, prototypic pallidal neurons, defined by Nkx2-1 expression, preferentially innervate parvalbumin- and somatostatin-expressing interneurons. These data reveal a structured and selective organization of pallidostriatal projections, suggesting that distinct classes of pallidal neurons modulate striatal circuits through complementary pathways. Mapping these connections is key to understanding how basal ganglia networks coordinate motor control.

neuroscience↗

bioRxiv2025

A molecular atlas of cell-type specific signatures in the parkinsonian striatum.

The progressive degeneration of dopaminergic projections to the striatum is a key disease mechanism in Parkinsons disease (PD). To define the cellular landscape in the parkinsonian striatum, we mapped the cell-type specific transcriptional landscape in early and progressive PD mouse models and in human PD stages. Our analyses revealed substantial transcriptomic changes across both neuronal and glial populations, with astrocytes and oligodendrocytes exhibiting distinct disease-associated gene expression profiles. Notably, progressive dopamine depletion uncovered differential neuronal vulnerability, identifying eccentric striatal projection neurons (SPNs) and Chst9-expressing direct-pathway SPNs as among the most resilient subtypes in both species. This cross-species resource establishes a comprehensive framework for investigating cell-state dynamics in the parkinsonian striatum and uncovers selectively vulnerable and resistant cell types that can inspire new therapeutic strategies.

neuroscience↗

bioRxiv2024

Anxa1+ dopamine neuron vulnerability defines prodromal Parkinson's disease bradykinesia and procedural motor learning impairment

Progressive degeneration of dopamine neurons (DANs) defines Parkinsons disease (PD). However, the identity and function of the most vulnerable DAN populations in prodromal PD remain undefined. Here, we identify substantia nigra DANs with Annexin A1 (Anxa1) expression as selectively vulnerable across multiple prodromal PD models and significantly reduced in patient-derived DANs. We found that Anxa1+ DANs have a unique functional profile, as they do not signal reward or reinforce actions, and they are not necessary for motivated behavior. Instead, activity of Anxa1+ DAN axons correlates with vigorous movements during self-paced exploration, yet their silencing only disrupts a subset of action sequences that mirror a PD bradykinesia profile. Importantly, Anxa1+ DANs are essential for procedural learning in a maze task and for motor learning of dexterous actions. These findings establish the early vulnerability of Anxa1+ DANs in PD, whose function can explain prodromal bradykinesia and impairments in procedural motor learning.

neuroscience↗

bioRxiv2024

A striosomal accumbens pathway drives compulsive seeking behaviors through an aversive Esr1+ hypothalamic-habenula circuit.

The lateral hypothalamic area (LHA) integrates external stimuli with internal states to drive the choice between competing innate or value-driven motivated behaviors. Projections from the LHA to the lateral habenula (LHb) shape internal states, with excitatory estrogen receptor 1-expressing (Esr1+) LHA-LHb neurons driving aversive responses and sustained negative states. Here, we identify and functionally characterize a specific projection from the nucleus accumbens (ACB) that targets Esr1+ LHA-LHb neurons. Using cell-type-specific tracing of monosynaptic inputs, single-nucleus RNA sequencing, and neuroanatomical mapping, we demonstrate that the Esr1+ LHA-LHb pathway receives a major input from a striosomal Tac1+/Tshz1+/Oprm1+ ACB neuron subtype. Intersectional cell-type-specific and input-output defined optogenetic manipulation of this ACB-LHA-LHb pathway revealed its role in signaling aversion after repeated activation, with the negative behavioral state being dependent on recruitment of Esr1+ LHA-LHb neurons. Importantly, we found that activation of the D1+ ACB-LHA pathway drives reward-independent compulsive-like seeking behaviors, expressed as compulsive digging or poking behaviors. We found that these complex yet stereotyped behaviors compete with highly motivated states and can override the need for natural rewards or social stimuli. Our findings reveal a discrete striosomal Tac1+ ACB projection targeting the aversive Esr1+ LHA-LHb pathway as a key circuit that promotes compulsive seeking behaviors over goal-directed actions.

neuroscience↗

bioRxiv2024

Striosomes Target Nigral Dopamine-Containing Neurons via Direct-D1 and Indirect-D2 Pathways Paralleling Classic Direct-Indirect Basal Ganglia Systems

Balanced activity of canonical direct D1 and indirect D2 basal ganglia pathways is considered a core requirement for normal movement, and their imbalance is an etiologic factor in movement and neuropsychiatric disorders. We present evidence for a conceptually equivalent pair of direct-D1 and indirect-D2 pathways that arise from striatal projection neurons (SPNs) of the striosome compartment rather than from SPNs of the matrix, as do the canonical pathways. These S-D1 and S-D2 striosomal pathways target substantia nigra dopamine-containing neurons instead of basal ganglia motor output nuclei. They modulate movement oppositely to the modulation by the canonical pathways: S-D1 is inhibitory and S-D2 is excitatory. The S-D1 and S-D2 circuits likely influence motivation for learning and action, complementing and reorienting canonical pathway modulation. A major conceptual reformulation of the classic direct-indirect pathway model of basal ganglia function is needed, as well as reconsideration of the effects of D2-targeting therapeutic drugs. HIGHLIGHTSO_LIDirect S-D1 and Indirect S-D2 striosomal pathways target SNpc dopamine cells C_LIO_LIThe S-D2 indirect pathway targets a distinct central external pallidal zone (cGPe) C_LIO_LIStimulation of S-D2 increases, of S-D1 decreases, striatal dopamine and movement C_LIO_LIS-D1 SPNs activity brackets task, inverse to a mid-task peak of dopamine release C_LI

neuroscience↗

bioRxiv2023

Sensorimotor Integration Supporting Perception Requires Syngap1 Expression in Cortex

Perception, a cognitive construct, emerges through sensorimotor integration (SMI). The genetic mechanisms that shape SMI required for perception are unknown. Here, we demonstrate in mice that expression of the autism/intellectual disability gene, Syngap1, in cortical excitatory neurons is required for formation of somatomotor networks that promote SMI-mediated perception. Cortical Syngap1 expression was necessary and sufficient for setting tactile sensitivity, sustaining tactile object exploration, and promoting tactile learning. Mice with deficient Syngap1 expression exhibited impaired neural dynamics induced by exploratory touches within a cortical-thalamic network known to promote attention and perception. Disrupted neuronal dynamics were associated with circuit-specific long-range synaptic connectivity abnormalities. Our data support a model where autonomous Syngap1 expression in cortical excitatory neurons promotes cognitive abilities through assembly of circuits that integrate temporally-overlapping sensory and motor signals, a process that promotes perception and attention. These data provide systems-level insights into the robust association between Syngap1 expression and cognitive ability.

neuroscience↗

bioRxiv2023

Local recurrent circuits modulate visual center and surround interactions in the mouse superior colliculus

Center-surround interactions are fundamental to visual saliency computation, but debate continues over whether and how subcortical visual circuits actively contribute. To address this, we developed an optogenetic approach to delineate the visual center and surround zones of individual neurons in the superficial layer of the superior colliculus (SCs) using only retinal ganglion cell input. Using whole-cell recordings, we demonstrate that surround network activation suppresses center excitability, indicating that SCs circuitry is self-sufficient in driving center-surround dynamics. Through cell-type-specific trans-synaptic tracing and large-scale modeling, we identified an SCs-based circuit with two key motifs driving surround modulation: recurrent excitation and feedback inhibition. We propose that subcortical visual circuits in the SCs have evolved to perform surround suppression alongside retinal and cortical suppression, facilitating the distribution of parallel saliency computations across different levels. Significance statementThis study questions the notion that the superior colliculus (SC) merely acts as a passive recipient of saliency information from upstream circuits. We demonstrate that the SC can independently generate center-surround interactions that could contribute to visual saliency through local circuits without top-down input. This ability represents a computation that has been conserved since the dawn of vertebrate evolution. By mapping these interactions, we reveal that the mouse SC actively induces visual surround suppression. These findings suggest that phylogenetically older circuits in the SC may play a more independent role in active vision than previously acknowledged, prompting a reevaluation of visual saliency processing across subcortical brain regions.

neuroscience↗

bioRxiv2022

Esr1+ hypothalamic-habenula neurons shape aversive states.

Excitatory projections from the lateral hypothalamic area (LHA) to the lateral habenula (LHb) drive aversive responses. We used Patch-seq guided multimodal classification to define the structural and functional heterogeneity of the LHA-LHb pathway. Our classification identified six glutamatergic neuron types with unique electrophysiological properties, molecular profiles, and projection patterns. We found that genetically-defined LHA-LHb neurons signal distinct aspects of emotional or naturalistic behaviors: Esr1+ LHA-LHb neurons induce aversion, whereas Npy+ LHA-LHb neurons control rearing behavior. Repeated optogenetic drive of Esr1+ LHA-LHb neurons induces a behaviorally persistent aversive state, and large-scale recordings showed a region-specific neural representation of the aversive state in the prelimbic region of the prefrontal cortex. We further found that exposure to unpredictable mild shocks induced a sex-specific sensitivity to develop a stress state in female mice, which was associated with a specific shift in the intrinsic properties of bursting-type Esr1+ LHA-LHb neurons. In summary, we describe the diversity of LHA-LHb neuron types, and provide evidence for the role of Esr1+ neurons in aversion and sexually dimorphic stress sensitivity.

neuroscience↗

bioRxiv2022

Sst+ GPi output neurons provide direct feedback to key nodes of the basal ganglia and drive behavioral flexibility.

The internal globus pallidus (GPi) is a basal ganglia output nucleus with separate projections to the thalamus and the lateral habenula (LHb). Here, we show a GPi subtype with projections to LHb (GPi-LHb), genetically defined based on glutamate/GABA co-transmission and somatostatin (Sst) expression, also projects back to key nodes in the basal ganglia: the external globus pallidus (GPe), the striatal striosomes, and dopamine neurons in the substantia nigra. We found that the Sst+ GPi population showed strong movement and direction-specific selectivity in a goal-directed choice task, but not during self-paced exploration, and did not signal prediction errors or outcome modulation. During goal-directed behavior, the Sst+ GPi activity slowly evolved with learning of correct choice actions and genetic silencing disrupted the ability to update choice behavior following a task rule reversal. In summary, we have found that Sst+ GPi neurons establish a wide feedback network in the basal ganglia and drive behavioral flexibility.

neuroscience↗

bioRxiv2020

A selective projection from the subthalamic nucleus to parvalbumin-expressing interneurons of the striatum

The striatum and subthalamic nucleus (STN) are considered to be the primary input nuclei of the basal ganglia. Projection neurons of both striatum and STN can extensively interact with other basal ganglia nuclei, and there is growing anatomical evidence of direct axonal connections from the STN to striatum. There remains, however, a pressing need to elucidate the organization and impact of these subthalamostriatal projections in the context of the diverse cell types constituting the striatum. To address this, we carried out monosynaptic retrograde tracing from genetically-defined populations of dorsal striatal neurons in adult male and female mice, quantifying the connectivity from STN neurons to spiny projection neurons, GABAergic interneurons, and cholinergic interneurons. In parallel, we used a combination of ex vivo electrophysiology and optogenetics to characterize the responses of a complementary range of dorsal striatal neuron types to activation of STN axons. Our tracing studies showed that the connectivity from STN neurons to striatal parvalbumin-expressing interneurons is significantly higher (~ four-to eight-fold) than that from STN to any of the four other striatal cell types examined. In agreement, our recording experiments showed that parvalbumin-expressing interneurons, but not the other cell types tested, commonly exhibited robust monosynaptic excitatory responses to subthalamostriatal inputs. Taken together, our data collectively demonstrate that the subthalamostriatal projection is highly selective for target cell type. We conclude that glutamatergic STN neurons are positioned to directly and powerfully influence striatal activity dynamics by virtue of their enriched innervation of GABAergic parvalbumin-expressing interneurons.

neuroscience↗

bioRxiv2020

Replicability of spatial gene expression atlas data from the adult mouse brain

BackgroundSpatial gene expression is particularly interesting in the mammalian brain, with the potential to serve as a link between many data types. However, as with any type of expression data, cross-dataset benchmarking of spatial data is a crucial first step. Here, we assess the replicability, with reference to canonical brain sub-divisions, between the Allen Institutes in situ hybridization data from the adult mouse brain (ABA) and a similar dataset collected using Spatial Transcriptomics (ST). With the advent of tractable spatial techniques, for the first time we are able to benchmark the Allen Institutes whole-brain, whole-transcriptome spatial expression dataset with a second independent dataset that similarly spans the whole brain and transcriptome. ResultsWe use LASSO, linear regression, and correlation-based feature selection in a supervised learning framework to classify expression samples relative to their assayed location. We show that Allen reference atlas labels are classifiable using transcription, but that performance is higher in the ABA than ST. Further, models trained in one dataset and tested in the opposite dataset do not reproduce classification performance bi-directionally. Finally, while an identifying expression profile can be found for a given brain area, it does not generalize to the opposite dataset. ConclusionsIn general, we found that canonical brain area labels are classifiable in gene expression space within dataset and that our observed performance is not merely reflecting physical distance in the brain. However, we also show that cross-platform classification is not robust. Emerging spatial datasets from the mouse brain will allow further characterization of cross-dataset replicability.

genomics↗

bioRxiv2020

A critical role for trkB signaling in the adult function of parvalbumin interneurons and prefrontal network dynamics

Inhibitory interneurons expressing parvalbumin (PV) in the prefrontal cortex (PFC) are central to excitatory/inhibitory (E/I) balance, generation of gamma oscillations, and cognition. Dysfunction of PV interneurons disrupts information processing and cognitive behavior. Tyrosine receptor kinase B (trkB) signaling is known to regulate the differentiation and maturation of cortical PV interneurons during development, but is also suggested to be involved in the activity and network functions of PV interneurons in the adult brain. Using a novel viral strategy for cell-type and region-specific expression of a dominant negative trkB in adult mice, we show that reduced trkB signaling in PV interneurons in the PFC leads to pronounced morphological, physiological, and behavioral changes. Our results provide evidence for a critical role of trkB signaling in the function of PV interneurons in the adult brain, local network activities central to prefrontal circuit dynamics, and cognitive behavior.

neuroscience↗

bioRxiv2020

Complete representation of action space and value in all striatal pathways.

The dorsal striatum plays a central role in motor and decision programs, such as the selection and execution of particular actions and the evaluation of their outcomes. A standard model has emerged where distinct output pathways encode separate motor-action signals, including selection-evaluation division in the matrix versus patch compartments. We used large-scale cell-type specific calcium imaging during motor and decision behaviors to determine and contrast the activity of individual striatal projection neurons (SPNs) belonging to one of the three major output pathways in the dorsomedial striatum - patch Oprm1+ SPNs versus the D1+ direct and A2A+ indirect pathway. We found that Oprm1+ SPNs were tuned to a number of different behavioral categories, such as to different movements, or to discrete actions and decisions in a two-choice task, and these complex representations were found to the same extent in all three striatal output pathways. The sharp tuning of individual SPNs was highly stereotyped over time while performing a specific task, but the tuning profile remapped between different behavioral contexts. In addition to action representations, SPNs showed pathway-independent representation of decision-variables such as the trial strategy and the action value. We propose that all three major output pathways in the dorsomedial striatum share a similarly complete representation of the entire action space, including task- and phase-specific signals of action value and choice.

neuroscience↗

bioRxiv2019

Molecular Atlas Of The Adult Mouse Brain

Brain maps are essential for integrating information and interpreting the structure-function relationship of circuits and behavior. We aimed to generate a systematic classification of the adult mouse brain organization based on unbiased extraction of spatially-defining features. Applying whole-brain spatial transcriptomics, we captured the gene expression signatures to define the spatial organization of molecularly discrete subregions. We found that the molecular code contained sufficiently detailed information to directly deduce the complex spatial organization of the brain. This unsupervised molecular classification revealed new area- and layer-specific subregions, for example in isocortex and hippocampus, and a new division of striatum. The whole-brain molecular atlas further supports the identification of the spatial origin of single neurons using their gene expression profile, and forms the foundation to define a minimal gene set - a brain palette - that is sufficient to spatially annotate the adult brain. In summary, we have established a new molecular atlas to formally define the identity of brain regions, and a molecular code for mapping and targeting of discrete neuroanatomical domains.

neuroscience↗

bioRxiv2019

Brain-wide genetic mapping identifies the indusium griseum as a prenatal and shared target of pharmacologically-unrelated psychostimulants

Psychostimulant use is an ever-increasing socioeconomic burden, including a dramatic rise during pregnancy. Nevertheless, brain-wide effects of psychostimulant exposure are incompletely understood. Here, we performed Fos-CreERT2-based activity mapping, correlated for pregnant mouse dams and their fetuses with amphetamine, nicotine and caffeine applied acutely during mid-gestation. While light-sheet microscopy-assisted intact tissue imaging revealed drug- and age-specific neuronal activation, the indusium griseum (IG) appeared indiscriminately affected. By using GAD67gfp/+ mice we subdivided the IG into a dorsolateral domain populated by GABA interneurons and a ventromedial segment containing glutamatergic neurons, many showing drug-induced activation and sequentially expressing Pou3f3/Brn1 and secretagogin (Scgn) during differentiation. We then combined Patch-seq and circuit mapping to show that the ventromedial IG is a quasi-continuum of glutamatergic neurons (IG-Vglut1+) reminiscent to dentate granule cells in both rodents and humans, whose dendrites emanate perpendicularly towards, while their axons course parallel with the superior longitudinal fissure. IG-Vglut1+ neurons receive Vglut1+ and Vglut2+ excitatory afferents that topologically segregate along their somatodendritic axis. In turn, their efferents terminate in the olfactory bulb, thus being integral to a multi-synaptic circuit that could feed information antiparallel to the olfactory-cortical pathway. In IG-Vglut1+ neurons, prenatal psychostimulant exposure delayed the onset of Scgn expression. Genetic ablation of Scgn was then found to sensitize adult mice towards methamphetamine-induced epilepsy, suggesting a role for this Ca2+-binding protein in scaling IG-Vglut1+ neuronal excitability. Overall, our study identifies brain-wide targets of the most common psychostimulants, among which Scgn+/Vglut1+ neurons of the IG link limbic and olfactory circuits.\n\nSignificance statementDrug abuse during pregnancy is a significant socioeconomic problem. The use of psychostimulants is particularly common during pregnancy even though a risk to the developing fetus is significant. Here, we show that short-lived exposure to amphetamine, nicotine and caffeine during pregnancy induces neuronal activation in the fetal brain with the indusium griseum (IG), a brain area situated parallel to the central surface of the cortical hemispheres, becoming indiscriminately activated. By using mouse genetics, we find that psychostimulants preferentially target glutamatergic IG neurons, and delay their differentiation postnatally. Notably, the expressional onset of secretagogin, a Ca2+-sensor amenable for synaptic integration, is deregulated. This is significant because these neurons are integral to a multi-synaptic neuronal pathway that links limbic and olfactory circuits. As such, genetic deletion of secretagogin brings about heightened sensitivity to psychostimulants, manifesting as epileptiform discharges. Cumulatively, we describe a novel psychostimulant-sensitive neuronal subtype and its circuit arrangement whose developmental delay seems critical for behavioral abnormalities in offspring prenatally exposed to the most common psychostimulants.

neuroscience↗

bioRxiv2019

A Spatiomolecular Map of the Striatum.

The striatum is organized into two major outputs formed by striatal projection neuron (SPN) subtypes with distinct molecular identities. In addition, the histochemical division into patch and matrix compartments represents an additional spatial organization, proposed to mirror a functional specialization in a motor-motivation dimension. To map the molecular diversity of SPNs in the context of the patch and matrix division, we genetically labeled mu-opioid receptor (Oprm1) expressing striatal neurons and performed single-nucleus RNA sequencing (snRNA-seq). This allowed us to establish new molecular definitions of the patch-matrix compartments, resulting in a molecular code for mapping patch SPNs at the cellular level. In addition, Oprm1 expression labeled exopatch SPNs, which we found to be molecularly distinct from both patch as well as neighboring matrix SPNs, thereby forming a separate molecular entity. At the cell-type level, we found an unexpected SPN diversity, leading to the identification of a new Col11a1+ striatonigral SPN type. At the tissue level, we found that mapping the spatial expression of a number of markers revealed new definitions of spatial domains in the striatum, which were conserved in the non-human primate brain. Interestingly, the spatial markers were cell-type independent and instead represented a spatial code that was found across all SPNs within a spatially restricted domain. This spatiomolecular map establishes a formal system for targeting and studying the striatal subregions and SPNs subtypes, beyond the classical striatonigral and striatopallidal division.

neuroscience↗