Biology subjects

Lin, I.

Publications and source records attributed to Lin, I..

5 recordsLinked to original sources

bioRxiv2023

Neuronal PAS domain 1 identifies a major subpopulation of wakefulness-promoting GABAergic neurons in basal forebrain

Here we describe a novel group of basal forebrain (BF) neurons expressing neuronal PAS domain 1 (Npas1), a developmental transcription factor linked to neuropsychiatric disorders. Immunohistochemical staining in Npas1-cre-2A-TdTomato mice revealed BF Npas1+ neurons are distinct from well-studied parvalbumin or cholinergic neurons. Npas1 staining in GAD67-GFP knock-in mice confirmed that the vast majority of Npas1+ neurons are GABAergic, with minimal colocalization with glutamatergic neurons in vGlut1-cre-tdTomato or vGlut2-cre-tdTomato mice. The density of Npas1+ neurons was high, 5-6 times that of neighboring cholinergic, parvalbumin or glutamatergic neurons. Anterograde tracing identified prominent projections of BF Npas1+ neurons to brain regions involved in sleep-wake control, motivated behaviors and olfaction such as the lateral hypothalamus, lateral habenula, nucleus accumbens shell, ventral tegmental area and olfactory bulb. Chemogenetic activation of BF Npas1+ neurons in the light (inactive) period increased the amount of wakefulness and the latency to sleep for 2-3 hr, due to an increase in long wake bouts and short NREM sleep bouts. Non-REM slow-wave (0-1.5 Hz) and sigma (9-15 Hz) power, as well as sleep spindle density, amplitude and duration, were reduced, reminiscent of findings in several neuropsychiatric disorders. Together with previous findings implicating BF Npas1+ neurons in stress responsiveness, the anatomical projections of BF Npas1+ neurons and the effect of activating them suggest a possible role for BF Npas1+ neurons in motivationally-driven wakefulness and stress-induced insomnia. Identification of this major subpopulation of BF GABAergic neurons will facilitate studies of their role in sleep disorders, dementia and other neuropsychiatric conditions involving BF. SIGNIFICANCE STATEMENTWe characterize a group of basal forebrain (BF) neurons in the mouse expressing neuronal PAS domain 1 (Npas1), a developmental transcription factor linked to neuropsychiatric disorders. BF Npas1+ neurons are a major subset of GABAergic neurons distinct and more numerous than cholinergic, parvalbumin or glutamate neurons. BF Npas1+ neurons target brain areas involved in arousal, motivation and olfaction. Activation of BF Npas1+ neurons in the light (inactive) period increased wakefulness and the latency to sleep due to increased long wake bouts. Non-REM sleep slow waves and spindles were reduced reminiscent of findings in several neuropsychiatric disorders. Identification of this major subpopulation of BF GABAergic wake-promoting neurons will allow studies of their role in insomnia, dementia and other conditions involving BF.

neuroscience↗

bioRxiv2023

Ventral pallidum projections to the ventral tegmental area reinforce but do not invigorate reward-seeking behavior

Reward-predictive cues acquire motivating and reinforcing properties that contribute to the escalation and relapse of drug use in addiction. The ventral pallidum (VP) and ventral tegmental area (VTA) are two key nodes in brain reward circuitry implicated in addiction and necessary for the performance of cue-driven behavior. Evidence suggests that VP neurons projecting to the VTA (VP[->]VTA) promote cue-induced reinstatement of drug-seeking, but the mechanisms by which these neurons do so are undefined. In addition, the role of these neurons in the pursuit of non-drug reward is not known. In the current study, we used in vivo fiber photometry and optogenetics to record from and manipulate VP[->]VTA in rats performing a discriminative stimulus task (DS task) with sucrose reward to determine the fundamental role these neurons play in invigoration and reinforcement by reward and associated discriminative cues. We find that VP[->]VTA neurons are selectively active during reward consumption, that optogenetic stimulation of these neurons paired with reward consumption biases choice, and that VP[->]VTA optogenetic stimulation is reinforcing. Critically, we found no significant encoding of cue-elicited reward-seeking vigor and acute optogenetic stimulation of these neurons paired with cue onset did not enhance the probability or vigor of reward-seeking. Our results suggest that VP[->]VTA neurons are active during the consumption of natural reward and that this activity reinforces seeking behavior.

neuroscience↗

bioRxiv2022

Ventral pallidal GABAergic neuron calcium activity encodes cue-driven reward-seeking and persists in the absence of reward delivery

Reward-seeking behavior is often initiated by environmental cues that signal reward availability. This is a necessary behavioral response; however, cue reactivity and reward-seeking behavior can become maladaptive. To better understand how cue elicited reward-seeking becomes maladaptive, it is important to understand the neural circuits involved in assigning appetitive value to rewarding cues and actions. Ventral pallidum (VP) neurons are known to contribute to cue elicited reward-seeking behavior and have heterogeneous responses in a discriminative stimulus (DS) task. The VP neuronal subtypes and output pathways that encode distinct aspects of the DS task remain unknown. Here, we used an intersectional viral approach with fiber photometry to record bulk calcium activity in VP GABAergic (VP GABA) neurons in male and female rats as they learned and performed the DS task. We found that VP GABA neurons are excited by reward-predictive cues but not neutral cues, and that this response develops over time. We also found that this cue-evoked response predicts reward-seeking behavior. Additionally, we found increased VP GABA calcium activity at the time of expected reward delivery, which occurred even on trials when reward was omitted. Together, these findings suggest that VP GABA neurons encode reward expectation and calcium activity in these neurons is predictive of the vigor of cue-elicited reward-seeking.

neuroscience↗

bioRxiv2022

ASXL1 mutations that cause Bohring Opitz Syndrome (BOS) or acute myeloid leukemia share epigenomic and transcriptomic signatures

De novo, truncating variants of ASXL1 cause two distinct disorders: Bohring-Opitz Syndrome (BOS, OMIM #605039) a rare pediatric disorder characterized by multiorgan anomalies that disrupt normal brain, heart, and bone development causing severe intellectual disability or are somatic driver mutations causing acute myeloid leukemia(AML). Despite their distinct clinical presentations, we propose that ASXL1 mutations drive common epigenetic and transcriptomic dysregulation in BOS and AML. We analyzed DNA methylation (DNAm) and RNA-seq data from BOS patients (n=13) and controls (n=38) and publicly available DNAm of AML cases with (n=3) and without (n=3) ASXL1 mutations from The Cancer Genome Atlas (TCGA), and RNA-seq data from AML cases (n=27) from the Beat AML cohort. Using a DNA-methylation based episignature that we previously developed for BOS, we clustered AML, BOS and normal controls together. We showed that AML samples with ASXL1 mutations clustered closest to individuals with BOS, whereas individuals with AML without ASXL1 mutations clustered separately. We also observe common dysregulation of the transcriptome between BOS and AML with ASXL1 mutations compared to controls. Our transcriptomic analysis identified 821 significantly differentially expressed genes that were shared between both data sets and 74.9% showed differential expression in the same direction. BOS patients are rare and have some reports of tumors but no clear guidelines on cancer screening protocols. This represents the first direct comparison between distinct diseases that show common epigenetic and transcriptomic effects, and potentially common drug targets for patients harboring ASXL1 mutations on the epigenome and transcriptome. KEY POINTSO_LIAcute myeloid leukemias harboring somatic ASXL1 driver mutations and Bohring-Opitz syndrome caused by germline ASXL1 mutations share common epigenomic and transcriptomic dysregulation C_LIO_LIA gene-centric approach can inform molecular mechanisms across distinct disease types and point towards shared targetable pathways. C_LI

cancer biology↗

bioRxiv2022

Truncating ASXL1 mutations in Bohring-Opitz Syndrome dysregulate canonical and non-canonical Wnt Signaling

ASXL1 (Additional sex combs-like 1) plays key roles in epigenetic regulation of early developmental gene expression. De novo truncating mutations in ASXL1 cause Bohring-Opitz syndrome (BOS, OMIM #605039), a rare neurodevelopmental condition characterized by severe intellectual disabilities, characteristic facial features, hypertrichosis, increased risk of Wilms tumor, and variable congenital anomalies including heart defects and severe skeletal defects giving rise to a typical BOS posture. These BOS-causing ASXL1 variants are also high-prevalence somatic driver mutations in acute myeloid leukemia (AML). We use primary cells from BOS individuals (n = 18) and controls (n = 49) to dissect gene regulatory changes caused by ASXL1 mutations using comprehensive multi-omics assays for chromatin accessibility (ATAC-seq), DNA methylation, histone methylation binding, and transcriptome in peripheral blood and skin fibroblasts. Our data shows that regardless of cell type, ASXL1 mutations drive strong cross-tissue effects that disrupt multiple layers of the epigenome. The data showed a broad activation of canonical Wnt signaling at the transcriptional and protein levels and upregulation of VANGL2, a planar cell polarity pathway protein that acts through non-canonical Wnt signaling to direct tissue patterning and cell migration. This multi-omics approach identifies the core impact of ASXL1 mutations and therapeutic targets for BOS and myeloid leukemias. Brief summaryGermline ASXL1 mutations that cause Bohring Optiz syndrome disrupt the epigenome and dysregulate gene expression resulting in activation of canonical and non-canonical Wnt signaling pathways.

genetics↗