Biology subjects

Galvan, A.

Publications and source records attributed to Galvan, A..

13 recordsLinked to original sources

bioRxiv2025

A Multimodal Atlas Reveals the Anatomical Distribution of Medium Spiny Neuron Subtypes and a Novel RGS6+ Population in the Primate Striatum

The primate striatum and its principal neuron type, the medium spiny neuron (MSN), integrate cortical and subcortical signals related to movement, cognition, and emotion. These signals are processed through cell type specific circuits traditionally defined by MSN dopamine receptor expression. However, classification by dopamine receptor type alone fails to fully specify MSN diversity and falls short of capturing the functional complexity of the striatum. Here, we combined single-nucleus multi-omic sequencing and high-plex spatial transcriptomics to build a comprehensive atlas of MSNs in the macaque striatum. Using multi-omic sequencing, we profiled MSNs across four anatomically and functionally defined territories, and we mapped these subtypes back into their anatomical context by integrating the multi-omic data with [~]5.4 million spatially resolved cells sampled across the full rostral-caudal and dorsal-ventral extent of the striatum. This approach revealed two previously undocumented ventral striatum (VS) subtypes, D1-VS-RGS6 and D2-VS-RGS6, which are molecularly distinct from known ventral striatal MSNs yet share core limbic features. We also uncovered gradients in matrix-compartment cell types along the rostral-caudal axis. Finally, by integrating MSN subtype-specific transcriptomes and ATAC-seq-derived regulatory annotations with human GWAS data, we demonstrate strong, cell-type-specific enrichment of polygenic risk for Parkinsons disease, substance use disorders, and psychiatric and cognitive traits, including a striking association of D2-VS-RGS6 with schizophrenia and bipolar disorder. Together, this multimodal atlas provides a foundation for linking primate striatal cell types to circuit function and disease mechanisms. HIGHTLIGHTSO_LIMultimodal analysis of NHP striatum reveals heterogeneous cell type distribution C_LIO_LITwo previously uncharacterized MSN subtypes in the ventral striatum express RGS6 C_LIO_LIVentral striatum cell types exhibit similar characteristics across the Rostro-Caudal axis C_LIO_LINHP cell types show strong, cell type specific associations to genomic disease predictors C_LI

neuroscience↗

bioRxiv2024

MICROENDOSCOPIC CALCIUM IMAGING IN SUPPLEMENTARY MOTOR AREA AND PRIMARY MOTOR CORTEX OF RHESUS MACAQUES AT REST AND DURING ARM MOVEMENT

The study of motor cortices in non-human primates is relevant to our understanding of human motor control, both in healthy conditions and in movement disorders. Calcium imaging and miniature microscopes allow the study of multiple genetically identified neurons with excellent spatial resolution. We used this method to examine activity patterns of projection neurons in deep layers of the supplementary motor (SMA) and primary motor areas (M1) in four rhesus macaques. We implanted gradient index lenses and expressed GCaMP6f to image calcium transients while the animals were at rest or engaged in an arm reaching task. We tracked the activity of SMA and M1 neurons across conditions, examined cell pairs for synchronous activity, and assessed whether SMA and M1 neuronal activation followed specific sequential activation patterns. We demonstrate the value of in vivo calcium imaging for studying patterns of activity in groups of corticofugal neurons in SMA and M1. HIGHLIGHTSO_LIUse of one-photon miniature microscopes and microendoscopic calcium imaging to study the activity of cortical projection neurons in the supplementary motor area (SMA) and primary motor cortex (M1) of rhesus macaques at rest or performing simple arm reaches. C_LIO_LICalcium transients were related to arm reaches and showed directional sensitivity in a proportion of cells in SMA and M1. C_LIO_LISubsets of cell pairs showed coactivation in SMA and M1 during rest and reaching tasks. The strength of coactivity was not related to the distance between cells. C_LIO_LISMA and M1 neurons displayed sequential activation patterns. C_LIO_LIWe demonstrated that microendoscopic calcium imaging can be used to assess dynamic activity within genetically identified cell populations in deep layers of SMA and M1. C_LI

neuroscience↗

bioRxiv2023

DREADD-mediated amygdala activation is sufficient to induce anxiety-like responses in young nonhuman primates

Anxiety disorders are among the most prevalent psychiatric disorders, with symptoms often beginning early in life. To model the pathophysiology of human pathological anxiety, we utilized Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in a nonhuman primate model of anxious temperament to selectively increase neuronal activity of the amygdala. Subjects included 10 young rhesus macaques; 5 received bilateral infusions of AAV5-hSyn-HA-hM3Dq into the dorsal amygdala, and 5 served as controls. Subjects underwent behavioral testing in the human intruder paradigm following clozapine or vehicle administration, prior to and following surgery. Behavioral results indicated that clozapine treatment post-surgery increased freezing across different threat-related contexts in hM3Dq subjects. This effect was again observed approximately 1.9 years following surgery, indicating the long-term functional capacity of DREADD-induced neuronal activation. [11C]deschloroclozapine PET imaging demonstrated amygdala hM3Dq-HA specific binding, and immunohistochemistry revealed that hM3Dq-HA expression was most prominent in basolateral nuclei. Electron microscopy confirmed expression was predominantly on neuronal membranes. Together, these data demonstrate that activation of primate amygdala neurons is sufficient to induce increased anxiety-related behaviors, which could serve as a model to investigate pathological anxiety in humans.

neuroscience↗

bioRxiv2023

Draft genome sequence of Microbacterium fakhimi sp. nov., a novel bacterium associated with the alga Chlamydomonas reinhardtii

Microbacterium fakhimi sp. nov. has been isolated from a contaminated algal culture (Chlamydomonas reinhardtii). Its genome has been fully sequenced (3,753,259 base pairs) and a tentative annotation is provided (3,704 genes). Both, genome information and growth tests suggest that M. fakhimi sp. nov. is auxotroph for biotin and thiamine and unable to use sulfate as sulfur (S) source. S-reduced forms, such as methionine and cysteine can support M. fakhimi sp. nov. growth. The potential biotechnological interest of this bacteria is discussed here and in a related research paper (Fakhimi et al., 2023b).

microbiology↗

bioRxiv2023

Chlamydomonas reinhardtii and Microbacterium fakhimi sp. nov., a mutualistic association that favor sustainable hydrogen production.

A multispecies bacterial community including Microbacterium forte sp. nov., Stenotrophomonas goyi sp. nov., and Bacillus cereus greatly promoted sustained hydrogen production by the microalga Chlamydomonas reinhardtii when cocultivated in mannitol- and yeast extract-containing medium (up to 313 mL{middle dot}L-1). Alga viability was also largely prolonged in the cocultures (>45 days) without any nutrient supplementation. Among the bacterial community, Microbacterium forte sp. nov. was the main responsible for the hydrogen production improvement. Nonetheless, the use of the entire bacterial community allowed a better growth of the alga during hydrogen production. Chlamydomonas reinhardtii and Microbacterium forte sp. nov. established a mutualistic association, based on the release of ammonium and acetic acid from the bacterium, while the alga provided sulfur-containing metabolites and complemented the bacterial auxotrophy for biotin and thiamine. This study uncovers the potential of the Chlamydomonas-bacteria consortia for durable and stable H2 production while allowing the simultaneous production of biomass.

microbiology↗

bioRxiv2022

Auxin production in the green alga Chlamydomonas involves an extracellular L-amino acid oxidase and supports algal-bacterial mutualism with methylobacteria

Interactions between algae and bacteria are widespread in aquatic and terrestrial ecosystems and play fundamental roles in nutrient cycling and biomass production. However, the chemical basis for many of these interactions is poorly characterized and understood. Recent studies have shown that the plant auxin indole acetic acid (IAA) can mediate chemical crosstalk between algae and bacteria, resembling its role in plant-bacterial associations. While algae have been shown to produce IAA, molecular pathways for IAA synthesis in algae have remained elusive. Here, we report a mechanism for IAA production from L-tryptophan mediated by the extracellular enzyme L-amino acid oxidase (LAO1) in the model alga Chlamydomonas reinhardtii. Under inorganic nitrogen limitation but in the presence of L-tryptophan and other amino acids, high levels of IAA are generated in an LAO1-dependent manner. Thus, LAO1 plays a dual role in scavenging nitrogen from L-amino acids and in producing the phytohormone IAA, which subsequently inhibits algal cell multiplication and chlorophyll degradation. We show that these inhibitory effects can be relieved in the presence of Methylobacterium spp., well-known plant growth-promoting bacteria (PGPB), whose growth is mutualistically enhanced by the presence of the alga. These findings reveal a complex interplay of microbial auxin production and degradation by algal-bacterial consortia under nitrogen limitation and draws attention to potential ecophysiological roles of terrestrial microalgae and PGPB in association with land plants.

microbiology↗

bioRxiv2022

Value-Based Neural Representations Predict Social Decision Preferences

Social decision-making is omnipresent in everyday life, carrying the potential for both positive and negative consequences for the decision-maker and those closest to them. While evidence suggests that decision makers use value-based heuristics to guide choice behavior, very little is known about how decision makers representations of other agents influence social choice behavior. We used multivariate pattern expression analyses on fMRI data to understand how value-based processes shape neural representations of those affected by ones social decisions and whether value-based encoding is associated with social decision preferences. We found that stronger value-based encoding of a given close other (e.g., parent) relative to a second close other (e.g., friend) was associated with a greater propensity to favor the former during subsequent social decision-making. These results are the first to our knowledge to explicitly show that value-based processes affect decision behavior via representations of close others.

neuroscience↗

bioRxiv2022

Basal Ganglia Neurons in Healthy and Parkinsonian Primates Generate Recurring Sequences of Spikes

The spiking activity of basal ganglia neurons can be characterized by summary statistics such as the average firing rate, or by measures of firing patterns, such as burst discharges, or oscillatory fluctuations of firing rates. Many of these features are altered by the presence of parkinsonism. This study examined another distinct attribute of firing activity, i.e., the occurrence of repeating sequences of inter-spike intervals. We studied this feature in extracellular electrophysiologic recordings that were made in the basal ganglia of Rhesus monkeys, before and after they had been rendered parkinsonian by treatment with the neurotoxin 1-methyl-4-phyl-1,2,3,6-tetrahydropyridine (MPTP). Neurons in both pallidal segments and in the subthalamic nucleus tended to fire in repeating sequences, typically 2 ISIs long (i.e., involving three spikes). In recordings that were 5000 inter-spike intervals long, 20-40% of spikes participated in one of many sequences with each ISI replicating the sequence pattern with a timing error of [≤]1%. Compared to similar analyses in shuffled representations of the same data, sequences were more common in the original representation of ISIs in the subthalamic nucleus and the external pallidal segment. Induction of parkinsonism reduced the proportion of sequence spikes in the external pallidum but increased it in the subthalamic nucleus. We found no relation between the sequence generation and the firing rate of neurons, and, at most, a weak correlation between sequence generation and the incidence of bursts. We conclude that basal ganglia neurons fire in recognizable sequences of ISIs, whose incidence is influenced by the induction of parkinsonism.

neuroscience↗

bioRxiv2022

Characterization of ultrapotent chemogenetic ligands for research applications in non-human primates

Chemogenetics is a technique for obtaining selective pharmacological control over a cell population by expressing an engineered receptor that is selectively activated by an exogenously administered ligand. A promising approach for neuronal modulation involves the use of "Pharmacologically Selective Actuator Modules" (PSAMs); these chemogenetic receptors are selectively activated by ultrapotent "Pharmacologically Selective Effector Molecules" (uPSEMs). To extend the use of PSAM/PSEMs to studies in nonhuman primates it is necessary to thoroughly characterize the efficacy and safety of these tools. We describe the time course and brain penetrance in rhesus monkeys of two compounds with promising binding specificity and efficacy profiles in in vitro studies, uPSEM792 and uPSEM817, after systemic administration. Rhesus macaques received subcutaneous (s.c.) or intravenous (i.v.) administration of uPSEM817(0.064 mg/kg) or uPSEM792 (0.87 mg/kg) and plasma and CSF samples were collected over the course of 48 hours. Both compounds exhibited good brain penetrance, relatively slow washout and negligible conversion to potential metabolites - varenicline or hydroxyvarenicline. In addition, we found that neither of these uPSEMs significantly altered heart rate or sleep. Our results indicate that both compounds are suitable candidates for neuroscience studies using PSAMs in nonhuman primates.

neuroscience↗

bioRxiv2021

Resting Parasympathetic Nervous System Activity is Associated with Greater Antiviral Gene Expression

Parasympathetic nervous system activity can downregulate inflammation, but it remains unclear how parasympathetic nervous system activity relates to antiviral activity. The present study examined associations between parasympathetic nervous system activity and cellular antiviral gene regulation in 90 adolescents (Mage = 16.3, SD = 0.7; 51.1% female) who provided blood samples and measures of cardiac respiratory sinus arrhythmia (RSA), twice, five weeks apart. Using a multilevel analytic framework, we found that higher RSA (an indicator of higher parasympathetic nervous system activity)--both at rest and during paced breathing--was associated with higher expression of Type I interferon (IFN) response genes in circulating leukocytes, even after adjusting for demographic and biological covariates. RSA was not associated with a parallel measure of inflammatory gene expression. These results identify a previously unrecognized immunoregulatory aspect of autonomic nervous system function and highlight a potential biological pathway by which parasympathetic nervous system activity may relate to health.

physiology↗

bioRxiv2019

Symptom Severity in Youths with Attention Deficit Hyperactivity Disorder Associated with Normalizing Effects of Treatment on fMRI Response during a Stop Signal Task

Inhibitory control deficits represent one of many core cognitive deficits in Attention-Deficit/Hyperactivity Disorder (ADHD). Neuroimaging studies suggest that individuals with ADHD exhibit atypical engagement of neural systems during response inhibition, but the exact nature of this phenotype is obscured by mixed findings. We tested whether drug-free youths with ADHD (n=30, ages 7-14 years, 10 female) exhibited atypical neural correlates of response inhibition, as measured with a stop signal task and fMRI, compared to matched controls. We next investigated medication effects and whether there was a relationship between symptom severity and medication effects on the fMRI-evaluated signal. Finally, we tested for a significant difference between effects of monotherapy and combined pharmacological treatment. Patients showed significantly slower stop signal response time and lower percent inhibition, but no significant differences in the neural correlates of response inhibition relative to controls. However, patients showed significantly elevated signal in frontostriatal regions during responses. Prefrontal signal in patients was positively associated with reaction time variability in patients, and change (medicated - drug free) in the prefrontal signal was significantly associated with symptom scores, such that patients with elevated symptoms had greater BOLD signal reduction following treatment. Medication significantly improved go response time median and variability as well as stop signal reaction time, but there were no significant effects of medication or treatment type on BOLD signal. These findings challenge the notion of frontostriatal hypoactivation during response inhibition as a biomarker for ADHD and suggest that symptom severity may be associated with response to medication.

neuroscience↗

bioRxiv2019

Chemogenetic inhibition of the amygdala modulates emotional behavior expression in infant rhesus monkeys

Manipulation of neuronal activity during the early postnatal period in monkeys has been largely limited to permanent lesion studies, which can be impacted by developmental plasticity leading to reorganization and compensation from other brain structures that can interfere with the interpretations of results. Chemogenetic tools, such as DREADDs (designer receptors exclusively activated by designer drugs), can transiently and reversibly activate or inactivate brain structures, avoiding the pitfalls of permanent lesions to better address important developmental neuroscience questions. We demonstrate that inhibitory DREADDs in the amygdala can be used to manipulate socioemotional behavior in infant monkeys. Two infant rhesus monkeys (1 male, 1 female) received AAV5-hSyn-HA-hM4Di-IRES-mCitrine injections bilaterally in the amygdala at 9 months of age. DREADD activation after systemic administration of either clozapine-N-oxide or low dose clozapine resulted in decreased freezing and anxiety on the human intruder paradigm and changed the looking patterns on a socioemotional attention eyetracking task, compared to vehicle administration. The DREADD-induced behaviors were reminiscent of, but not identical to, those seen after permanent lesions of the amygdala in infant monkeys, such that early amygdala lesions produce a more extensive array of behavioral changes in response to the human intruder task that were not seen with DREADD-evoked inhibition of this region. Our results support the notion that early permanent damage leads to brain reorganization manifesting in a broader impact on behavior. The current study provides a proof-of-principle that DREADDs can be used in young infant monkeys to transiently and reversibly manipulate behavior. Statement of SignificanceMany neurodevelopmental disorders exhibit abnormal structural or functional amygdala development and alterations in socioemotional behavior. To date, developmental neuroscience studies have relied on permanent lesions techniques to investigate how atypical amygdala development impacts socioemotional behaviors, which may not adequately recapitulate the role of amygdala dysfunction in the manifestation of aberrant behavior. The present study sought to demonstrate that the DREADDs (designer receptors exclusively activated by designer drugs) chemogenetic tool could transiently inhibit amygdala activity in infant monkeys resulting in alterations in socioemotional behavior. This proof-of-principle study supports the use of chemogenetics for developmental neuroscience research, providing an opportunity to broaden our understanding of how changes in neuronal activity across early postnatal development influences behavior and clinical symptoms.

neuroscience↗

bioRxiv2016

Dynamic flexibility in striatal-cortical circuits supports reinforcement learning

Complex learned behaviors must involve the integrated action of distributed brain circuits. While the contributions of individual regions to learning have been extensively investigated, understanding how distributed brain networks orchestrate their activity over the course of learning remains elusive. To address this gap, we used fMRI combined with tools from dynamic network neuroscience to obtain time-resolved descriptions of network coordination during reinforcement learning. We found that learning to associate visual cues with reward involves dynamic changes in network coupling between the striatum and distributed brain regions, including visual, orbitofrontal, and ventromedial prefrontal cortex. Moreover, we found that flexibility in striatal network dynamics correlates with participants learning rate and inverse temperature, two parameters derived from reinforcement learning models. Finally, we found that not all forms of learning relate to this circuit: episodic memory, measured in the same participants at the same time, was related to dynamic connectivity in distinct brain networks. These results suggest that dynamic changes in striatal-centered networks provide a mechanism for information integration during reinforcement learning.\n\nSignificance StatementLearning from the outcomes of actions-referred to as reinforcement learning-is an essential part of life. The roles of individual brain regions in reinforcement learning have been well characterized in terms of the updating of values for actions or sensory stimuli. Missing from this account, however, is a description of the manner in which different brain areas interact during learning to integrate sensory and value information. Here we characterize flexible striatal-cortical network dynamics that relate to reinforcement learning behavior.

neuroscience↗