Biology subjects

Mantas, I.

Publications and source records attributed to Mantas, I..

4 recordsLinked to original sources

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↗

bioRxiv2023

Transcriptomic atlas of midbrain dopamine neurons uncovers differential vulnerability in a Parkinsonism lesion model

Midbrain dopamine (mDA) neurons comprise diverse cells with unique innervation targets and functions. This is illustrated by the selective sensitivity of mDA neurons of the substantia nigra compacta (SNc) in patients with Parkinsons disease, while those in the ventral tegmental area (VTA) are relatively spared. Here we used single nuclei RNA sequencing (snRNA-seq) of approximately 70,000 mouse midbrain cells to build a high-resolution atlas of mouse mDA neuron diversity at the molecular level. The results showed that differences between mDA neuron groups could best be understood as a continuum without sharp differences between subtypes. Thus, we assigned mDA neurons to several "territories" and "neighborhoods" within a shifting gene expression landscape where boundaries are gradual rather than discrete. Based on the enriched gene expression patterns of these territories and neighborhoods, we were able to localize them in the adult mouse midbrain. Moreover, because the underlying mechanisms for the variable sensitivities of diverse mDA neurons to pathological insults are not well understood, we analyzed surviving neurons after partial 6-hydroxydopamine (6-OHDA) lesions to unravel gene expression patterns that correlate with mDA neuron vulnerability and resilience. Together, this atlas provides a basis for further studies on the neurophysiological role of mDA neurons in health and disease.

neuroscience↗