Biology subjects

Blake, D. T.

Publications and source records attributed to Blake, D. T..

6 recordsLinked to original sources

bioRxiv2024

Cortical Acetylcholine Response to Deep Brain Stimulation of the Basal Forebrain

BackgroundDeep brain stimulation (DBS), the direct electrical stimulation of neuronal tissue in the basal forebrain to enhance release of the neurotransmitter acetylcholine, is under consideration as a method to improve executive function in patients with dementia. While some small studies indicate a positive response in the clinical setting, the relationship between DBS and acetylcholine pharmacokinetics is incompletely understood. ObjectiveWe examined the cortical acetylcholine response to different stimulation parameters of the basal forebrain. Methods2-photon imaging was combined with deep brain stimulation. Stimulating electrodes were implanted in the subpallidal basal forebrain, and the ipsilateral somatosensory cortex was imaged. Acetylcholine activity was determined using the GRABACh-3.0 muscarinic acetylcholine receptor sensor, and blood vessels were imaged with Texas red. ResultsExperiments manipulating pulse train frequency demonstrated that integrated acetylcholine induced fluorescence was insensitive to frequency, and that peak levels were achieved with frequencies from 60 to 130 Hz. Altering pulse train length indicated that longer stimulation resulted in higher peaks and more activation with sublinear summation. The acetylcholinesterase inhibitor donepezil increased the peak response to 10s of stimulation at 60Hz, and the integrated response increased 57% with the 2 mg/kg dose, and 126% with the 4 mg/kg dose. Acetylcholine levels returned to baseline with a time constant of 14 to 18 seconds in all experiments. ConclusionsThese data demonstrate that acetylcholine receptor activation is insensitive to frequency between 60 and 130 Hz. High peak responses are achieved with up to 900 pulses. Donepezil increases total acetylcholine receptor activation associated with DBS but did not change temporal kinetics. The long time constants observed in the cerebral cortex add to the evidence supporting volume in addition to synaptic transmission. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=117 SRC="FIGDIR/small/605828v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@a06bborg.highwire.dtl.DTLVardef@4003f0org.highwire.dtl.DTLVardef@c286d1org.highwire.dtl.DTLVardef@1213d2c_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Intermittent stimulation of the basal forebrain improves working memory in aged nonhuman primates.

Brain aging contributes to cognitive decline and risk of dementia. Degeneration of the basal forebrain cholinergic system parallels these changes in aging, Alzheimers dementia, Parkinsons dementia, and Lewy body dementia, and thus is a common element linked to executive function across the lifespan and in disease states. Here, we tested the potential of one-hour daily intermittent basal forebrain stimulation to improve cognition in senescent monkeys, and its mechanisms of action. Stimulation in five animals improved working memory duration in 8-12 weeks across all animals, with peak improvements observed in the first four weeks. In an ensuing three month period without stimulation, improvements were retained. With additional stimulation, performance remained above baseline throughout the 15 months of the study. Studies with a cholinesterase inhibitor produced inconsistent improvements in behavior. One of five animals improved significantly. Manipulating the stimulation pattern demonstrated selectivity for both stimulation and recovery period duration. Brain stimulation led to acute increases in cerebrospinal levels of tissue plasminogen activator, which is an activating element for two brain neurotrophins, Nerve Growth Factor (NGF) and Brain-Derived Growth Factor (BDNF). Stimulation also led to improved glucose utilization in stimulated hemispheres relative to contralateral. Glucose utilization also consistently declines with aging and some dementias. Together, these findings suggest that intermittent stimulation of the nucleus basalis of Meynert improves executive function and reverses some aspects of brain aging. HighlightsO_LIThe basal forebrain and its cholinergic projections are the sole source of acetylcholine for the cortical mantle in primates and humans. C_LIO_LIForebrain function tracks cognitive loss throughout the adult lifespan. C_LIO_LIOne hour per day intermittent stimulation of this region improves executive function behaviors and plausibly reverses some aspects of brain aging, a large risk factor in dementias. C_LIO_LIThis stimulation exceeds impacts of standard pharmacotherapies, is enduring, recruits brain neurotrophic pathways and improves cortical glucose utilization. C_LI

neuroscience↗

bioRxiv2024

α7 nicotinic acetylcholine receptors are necessary for basal forebrain activation to increase expression of the nerve growth factor receptor TrkA

Activation of the basal forebrain leads to increases in the expression of the nerve growth factor receptor, Tropomyosin receptor kinase A (TrkA) and decreases in expression of the beta amyloid cleavage enzyme 1 (BACE1) in the cerebral cortex of both sexes of 5xFAD mice. The studies described in this report were designed to determine if these changes were dependent on acetylcholine receptors. Mice were stimulated unilaterally in the basal forebrain for two weeks. Animals were administered a cholinergic antagonist, or saline, 30 minutes prior to stimulation. Animals administered saline exhibited significant increases in TrkA expression and decreases in BACE1 in the stimulated hemisphere relative to the unstimulated. While both nonselective nicotinic and muscarinic acetylcholine receptor blockade attenuated the BACE1 decline, only the nicotinic receptor antagonism blocked the TrkA increase. Next, we applied selective nicotinic antagonists, and the 7 antagonist blocked the TrkA increases, but the 4{beta}2 antagonist did not. BACE1 declines were not blocked by either intervention. Mice with a loxP conditional knockout of the gene for the 7 nicotinic receptor were also employed in these studies. Animals were either stimulated bilaterally for two weeks, or left unstimulated. With or without stimulation, the expression of TrkA receptors was lower in the cortical region with the 7 nicotinic receptor knockdown. We thus conclude that 7 nicotinic receptor activation is necessary for normal expression of TrkA and increases caused by basal forebrain activation, while BACE1 declines caused by stimulation have dependency on a broader array of receptor subtypes.

neuroscience↗

bioRxiv2022

Cholinergic forebrain activation improves cognition, boosts neurotrophin receptors, and lowers Aβ42 levels in the cerebral cortex of 5xFAD mice.

The biological basis of Alzheimers dementia has been hypothesized in terms of basal forebrain cholinergic decline, and in terms reflecting the neuropathologies surrounding beta amyloid and tau. To shed light on the contributions of these different biological elements, we performed five month intermittent stimulation of the basal forebrain, which projects to the cortical mantle, in 5xFAD Alzheimers model mice and wild-type littermates, and subjected mice to behavioral testing and tissue analysis. The 5xFAD mice performed worse in water maze testing than their littermates. Stimulation improved both classes of mice, and removed performance differences between genotypes by the fifth testing day. Stimulated groups had two to four-fold increases in immunoblot measures of each of the neurotrophin receptors tropomyosin receptor kinase A and B. Stimulation also led to lower tissue A{beta}42 and beta amyloid cleavage enzyme 1 in 5xFAD mice. Despite the lack of strong direct projections from the basal forebrain stimulation region to the hippocampus, the hippocampal tissues in stimulated mice had more nerve growth factor receptor, and lower levels of beta secretase for amyloid. These data support a causal relation between forebrain cholinergic pathways and cognitive decline dependent on A{beta}42. Activation of cholinergic brain pathways improves neurotrophin pathways and reduces A{beta}42 accumulation. The recruitment of both classes of neurotrophin receptors in the process suggests a serine protease cleavage intermediary between cholinergic response and neurotrophin activation.

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bioRxiv2020

Training-induced prefrontal neuronal changes transfer between tasks

Training to improve working memory is associated with changes in prefrontal activation and confers lasting benefits, some of which generalize to untrained tasks, though the issue remains contentious and the neural substrate underlying such transfer are unknown. To assess how neural activity changes induced by training transfer across tasks, we recorded single units, multi-unit activity (MUA) and local field potentials (LFP) with chronic electrode arrays implanted in the prefrontal cortex of two monkeys, as they were trained to perform cognitive tasks. Mastering different tasks was associated with distinct changes in neural activity, which included redistribution of power across frequency bands in the LFP, recruitment of larger numbers of MUA sites, and increase or decrease of mean neural activity across single units. In every training phase, changes induced by the actively learned task transferred to an untrained control task, which remained the same across the training period. The results explicate the neural basis through which training can transfer across cognitive tasks.

neuroscience↗

bioRxiv2019

Nucleus Basalis Stimulation Stabilizes Attractor Networks and Enhances Task Representation in Prefrontal Cortex

Acetylcholine in the neocortex is critical for executive function. Degeneration of the basal forebrain cholinergic system is associated with cognitive decline in aging and Alzheimers disease. Cholinergic agonists and acetylcholinesterase inhibitors improve cognitive performance as does intermittent electrical stimulation of the cortical source of acetylcholine, the Nucleus Basalis (NB) of Meynert. Here we tested how NB stimulation improves working memory behavior and alters its neural code. NB stimulation increased dorsolateral prefrontal activity during the delay period of working memory tasks but did not strengthen phasic responses to the optimal visual stimulus of each neuron. Unexpectedly, improvement of behavioral performance was not the result of increased neural selectivity. Tuning of neuronal responses broadened, which rendered an attractor network more stable and filtered distracting visual stimuli more effectively. Thus, the effects of acetylcholine on prefrontal neural activity and selectivity in working memory contrast those of dopamine and stabilize neural ensembles based on neuromodulatory tone.

neuroscience↗