Biology subjects

McNally, J. M.

Publications and source records attributed to McNally, J. M..

7 recordsLinked to original sources

bioRxiv2026

Early Loss of Deep Restorative Sleep and Auditory Stimulus Evoked 40-Hz activity of Hippocampal Parvalbumin Neurons in the APP/PS1 Mouse Model of Alzheimer's Disease

Sleep abnormalities and dysfunction of gamma band (30-80 Hz) activity generated by parvalbumin (PV) interneurons are early characteristics of Alzheimers disease (AD) which correlate with the severity of amyloid-{beta} deposition (A{beta}) and cognitive impairment. However, the timing of these alterations in vivo with respect to disease progression is unclear. Here, in longitudinal recordings from APP/PS1/PV-cre (AD mice) from 3-6 months, we found reduced sleep slow-wave power (0.5-4 Hz) in hippocampus and medial prefrontal cortex in AD mice as young as 3 months old, compared to non-AD (PV-cre) mice, well before overt pathology. This finding was primarily due to reductions in the NREM delta range (1.5-4 Hz), a hallmark of restorative functions of sleep. In contrast, beta (15-30 Hz) power linked to insomnia was significantly higher across all sleep-wake states. Loss of deep NREM sleep was not compensated by an increase in NREM sleep time, instead NREM sleep during the dark (active) phase was slightly but significantly lower in AD mice. 40-Hz auditory steady-state responses and associated evoked calcium responses of hippocampal PV neurons recorded using fiber photometry were also impaired by 3 months old. However, Y-maze performance in 3- and 6-month-old AD mice was not significantly different from non-AD mice. These results reveal reduced deep sleep and PV-associated 40-Hz activity as very early changes amenable to early intervention occurring prior to cognitive deficits. Furthermore, they establish APP/PS1 mice as a good model to causally test the relationship between sleep, PV neuronal activity and amyloid-mediated pathology.

neuroscience↗

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↗

bioRxiv2021

Basal forebrain parvalbumin neurons modulate vigilant attention.

Attention is impaired in many neuropsychiatric disorders1 and by sleep disruption, leading to decreased workplace productivity and increased risk of accidents2-4. Thus, understanding the underlying neural substrates is important for developing treatments. The basal forebrain (BF) is a brain region which degenerates in dementia5-7 and is implicated in the negative effects of sleep disruption on vigilance and cognition8,9. Previous studies demonstrated that the BF controls cortical fast oscillations that underlie attention10-12 and revealed the important role of cholinergic neurons13-15. However, the role of other neurochemically defined BF subtypes is unknown. Recent work has shown that one population of BF GABAergic neurons containing the calcium-binding protein parvalbumin (PV) control cortical fast oscillations and arousals from sleep16-19 but their role in awake behavior is unclear. Thus, here we test the hypothesis that BF-PV neurons modulate vigilant attention in mice. A lever release version of the rodent psychomotor vigilance test (rPVT) was used to assess vigilant attention as measured by reaction time. Brief and continuous low power optogenetic excitation of BF-PV neurons (1s,473nm@5mW) that preceded the cue light signal by 0.5s improved vigilant attention as indicated by quicker reaction times. In contrast, both sleep deprivation (8h) and optogenetic inhibition of BF-PV neurons (1s,530nm@10mW) slowed reaction times. Importantly, BF-PV excitation rescued the reaction time deficits in sleep deprived mice. These findings reveal for the first time a role for BF-PV neurons in attention. HIGHLIGHTSO_LIOptogenetic methods tested the neural circuitry of vigilant attention in mice C_LIO_LIExcitation of basal forebrain parvalbumin neurons quickened reaction times C_LIO_LISleep deprivation or inhibition of parvalbumin neurons slowed reaction times C_LIO_LIExcitation of parvalbumin neurons rescued deficits produced by sleep deprivation C_LI

neuroscience↗

bioRxiv2020

CRISPR knockdown of GABAA alpha3 subunits on thalamic reticular neurons enhances deep sleep

Identification of mechanisms which increase deep sleep could lead to novel treatments which promote the restorative effects of sleep. Here, knockdown of the 3 GABAA-receptor subunit from parvalbumin neurons in the thalamic reticular nucleus using CRISPR-Cas9 gene editing increased the thalamocortical delta oscillations implicated in many health-promoting effects of sleep. Inhibitory synaptic currents were strongly reduced in vitro. Effects were most pronounced in the mouse sleep (light) period. Further analysis identified a novel deep-sleep state in mice prior to NREM-REM transitions which was preferentially affected by deletion of 3 subunits. Our results identify a functional role for GABAA receptors on Thalamic Reticular Nucleus neurons and suggest antagonism of 3 subunits as a strategy to enhance deep sleep. One Sentence SummarySelective genetic knockdown of the major subunit of GABAA receptors present in the thalamic reticular nucleus enhanced deep sleep in mice.

neuroscience↗

bioRxiv2020

Altered neural oscillations and behavior in a genetic mouse model of NMDA receptor hypofunction

IntroductionAbnormalities in electroencephalographic (EEG) biomarkers occur in patients with schizophrenia and those clinically at high risk for transition to psychosis and are associated with cognitive impairment. While the pathophysiology of schizophrenia remains poorly understood, converging evidence suggests N-methyl-D-aspartate receptor (NMDAR) hypofunction plays a central role and likely contributes to biomarker impairments. Thus, the characterization of such biomarkers is of significant interest for both the early diagnosis of schizophrenia and the development of novel treatments. MethodsWe utilized an established model of chronic NMDAR hypofunction, serine racemase knockout (SRKO) mice. In vivo EEG recording and behavioral analyses were performed on adult male and female SRKO mice and wild-type littermates to determine the impact of chronic NMDAR hypofunction on a battery of translationally-relevant electrophysiological biomarkers. ResultsSRKO mice displayed impairments in investigation-elicited gamma power that corresponded with reduced short-term social recognition. This impairment was associated with enhanced background (pre-investigation) broadband gamma activity that only appeared during social task performance. Additionally, SRKO mice exhibited sensory gating impairments, in both gamma power and event-related potential amplitude. However, other biomarkers such as the auditory steady-state response, sleep spindles, and state-specific power spectral density were generally neurotypical. ConclusionsSRKO mice provide a useful model to understand how chronic NMDAR hypofunction contributes to deficits in a subset of translationally-relevant EEG biomarkers that are altered in schizophrenia. Importantly, our gamma band findings support the hypothesis that an aberrant signal-to-noise ratio impairing cognition occurs with NMDAR hypofunction, which may be tied to impaired taskdependent alteration in functional connectivity.

neuroscience↗

bioRxiv2020

Characterization of basal forebrain glutamate neurons suggests a role in control of arousal and avoidance behavior

The basal forebrain (BF) is involved in arousal, attention, and reward processing but the role of individual BF subtypes is still being uncovered. Glutamatergic neurons are the least well-understood of the three major BF neurotransmitter phenotypes. Here we analyzed the distribution, size, calcium-binding protein content and projections of the major group of BF glutamate neurons expressing the vesicular glutamate transporter subtype 2 (vGluT2) and tested the functional effect of activating them. Mice expressing Cre recombinase under control of the vGluT2 promoter were crossed with a reporter strain expressing the red fluorescent protein, tdTomato, to generate vGluT2-cre-tdTomato mice. Immunohistochemical staining for choline acetyltransferase and a cross with mice expressing green fluorescent protein selectively in GABAergic neurons confirmed cholinergic, GABAergic and vGluT2+ neurons represent separate BF subpopulations. Subsets of BF vGluT2+ neurons expressed the calcium binding proteins calbindin or calretinin, suggesting that multiple subtypes of BF vGluT2+ neurons exist. Anterograde tracing using adeno-associated viral vectors expressing channelrhodopsin2- enhanced yellow fluorescent fusion proteins revealed major projections of BF vGluT2+ neurons to neighboring BF cholinergic and parvalbumin neurons, as well as to extra-BF areas involved in the control of arousal and regions responding to aversive or rewarding stimuli such as the lateral habenula and ventral tegmental area. Optogenetic activation of BF vGluT2 neurons in a place preference paradigm elicited a striking avoidance of the area where stimulation was given. Together with previous optogenetic findings suggesting an arousal-promoting role, our findings suggest BF vGluT2 neurons play a dual role in promoting wakefulness and avoidance behavior.

neuroscience↗

bioRxiv2019

Basal forebrain parvalbumin neurons mediate arousals from sleep induced by hypercarbia or auditory stimuli

Brief arousals from sleep in patients with sleep apnea and other disorders prevent restful sleep, and contribute to cognitive, metabolic and physiologic dysfunction. Little is currently known about which neural systems mediate these brief arousals, hindering the development of treatments. The basal forebrain (BF) receives inputs from many nuclei of the ascending arousal system. These inputs include the brainstem parabrachial neurons which promote arousal in response to elevated blood carbon dioxide levels, as seen in sleep apnea. Optical inhibition of the terminals of parabrachial neurons in the BF impairs cortical arousals to hypercarbia, but which cell types within the BF mediate cortical arousals in response to hypercarbia or other sensory stimuli is unknown. Here using optogenetic techniques in mice, we show that BF parvalbumin (PV) neurons fulfill several criteria for a system mediating brief arousals from sleep. Optical stimulation of BF PV neurons during the light period, when mice normally sleep, caused rapid transitions to wakefulness and increased wake bout durations. Unlike many other ascending arousal systems, arousals induced by stimulation of BF PV neurons were brief, resulting in only a small (13.6%) increase in the total amount of wakefulness. Bilateral optical inhibition of BF PV neurons increased the latency to arousal produced by hypercarbia or auditory stimuli. Thus, BF PV neurons are an important component of the brain circuitry which generates brief arousals from sleep in response to internal and external sensory stimuli.

neuroscience↗