Biology subjects

Hake, H. S.

Publications and source records attributed to Hake, H. S..

5 recordsLinked to original sources

bioRxiv2025

The Role of the Basal Ganglia in the Human Cognitive Architecture: A Dynamic Causal Modeling Comparison Across Tasks and Individuals

Researchers agree input from the basal ganglia (BG) to the prefrontal cortex (PFC) plays an important role in cognition, but they disagree on its computational properties. Theoretical models characterize the majority of BG input as either direct (directly transmitting information to the PFC), or modulatory (indirectly influencing PFC activity through the gating of signals from other cortical areas). To determine the computational nature of these BG-PFC inputs in cognition, we tested three alternative connectivity configurations (Direct, Modulatory, and Mixed) within a large-scale cognitive architecture. This architecture, the Common Model of Cognition, has been independently validated using fMRI data from the Human Connectome Project (HCP). The Direct model reflected the standard CMC configuration, featuring a bidirectional, direct connection between the BG and PFC modules. The Modulatory model removed this direct link, instead incorporating a unidirectional connection from the PFC to the BG and two modulatory pathways from the BG to the PFC that passed through other cortical modules. The Mixed model included both direct and modulatory connections. Using fMRI data from 200 HCP participants performing six cognitive tasks and one resting-state session, we applied Dynamic Causal Modeling (DCM) to estimate and compare the influence of these different BG-PFC connectivity patterns. Here, we show that for each of the six cognitive tasks and resting state, the Mixed model consistently outperformed the Direct and Modulatory models. The next best model depended on the specific cognitive task, suggesting the ability for the BG to flexibly adapt to various task demands. Taken together, the current data provide evidence for a likely set of core computations that the BG uses to differentially regulate cortical activity. Author SummaryThis study aimed to understand the nature of regulatory input from the basal ganglia to the prefrontal cortex in cognition using a neuro-computational approach. Three model architectures of basal ganglia connectivity were tested using fMRI data from 200 individuals during cognitive tasks and resting state sessions. Our findings indicate that the Mixed architecture, in which the basal ganglia can affect the prefrontal cortex both directly and indirectly, outperformed the Direct and Modulatory architectures across various cognitive tasks and resting state sessions. The results suggest that the basal ganglia likely uses a set of core computations to regulate cortical activity, which is present during task and task-free behavior.

neuroscience↗

bioRxiv2023

Efficient Memory Encoding Explains the Interactions Between Hippocampus Size, Individual Experience, and Clinical Outcomes: A Computational Model

The relationship between hippocampal volume and memory function has produced mixed results in neuroscience research, which suggests an additional influencing mechanism. To explore the role of an experience-dependent encoding mechanism, we developed an autoencoder model of the cortex-hippocampus loop and examined how its memory representation is affected by a penalty that prioritizes sparseness. We trained our model with the Fashion MNIST database and a loss function to modify synapses via backpropagation of mean squared recall error. The model exhibited experience-dependent efficient encoding, representing frequently-repeated objects with fewer neurons and smaller loss penalties; representations of similar sizes were found for objects repeated equally. Our findings clarify perplexing results from neurodevelopmental studies by linking increased hippocampal size and memory impairments in autism spectrum disorder (ASD) to decreased sparseness, and explaining dementia symptoms of forgetting with varied neuronal integrity. Our findings propose a novel model that connects observed relationships between hippocampal size and memory to the environmental demands and the underlying biological constraints, contributing to the development of a larger theory on experience-dependent encoding and storage and its failure. Author SummaryThe hippocampus is the brain region where memories are initially formed. A larger hippocampus seems to be associated with better memory performance, but this is not a static relationship; studies suggest that its size might grows with demand (e.g., the need to memorize more information) and that, in certain conditions, larger or smaller volumes of the hippocampus are not associated with better or worse memory. We demonstrate that it is possible to make sense of these findings by assuming that the hippocampus balances the need to correctly remember with the need to minimize resources used to store it, and that the hippocampal size might change as a function of memory demands (the characteristics of the information to memorize) and the underlying biology (e.g., the presence of hippocampal cell damage, or a reduction in hippocampal GABA receptors). We test this hypothesis by building a neural network model; the model correctly predicts existing, puzzling findings in the literature, and can even capture subtle interactions between different phenomena, such as predicting that individuals with Autism Spectrum Disorder would be more susceptible to memory loss in dementia.

neuroscience↗

bioRxiv2023

Inhibition of noradrenaline-dependent synaptic transmission in the dorsal raphe nucleus by alpha2-adrenergic receptors

In the central nervous system, noradrenaline transmission controls the degree to which we are awake, alert, and attentive. Aberrant noradrenaline transmission is associated with pathological forms of hyper- and hypo-arousal that present in numerous neuropsychiatric disorders often associated with dysfunction in serotonin transmission. In vivo, noradrenaline regulates the release of serotonin because noradrenergic input drives the serotonin neurons to fire action potentials via activation of excitatory 1-adrenergic receptors (1-AR). Despite the critical influence of noradrenaline on the activity of dorsal raphe serotonin neurons, the source of noradrenergic afferents has not been resolved and the presynaptic mechanisms that regulate noradrenaline-dependent synaptic transmission have not been described. Using an acute brain slice preparation from male and female mice and electrophysiological recordings from dorsal raphe serotonin neurons, we found that selective optogenetic activation of locus coeruleus terminals in the dorsal raphe was sufficient to produce an 1-AR-mediated excitatory postsynaptic current (1-AR-EPSC). Activation of inhibitory 2-adrenergic receptors (2-AR) with UK-14,304 eliminated the 1-AR-EPSC via presynaptic inhibition of noradrenaline release, likely via inhibition of voltage-gated calcium channels. In a subset of serotonin neurons, activation of postsynaptic 2-AR produced an outward current through activation of potassium conductance. Further, in vivo activation of 2-AR by systemic administration of clonidine reduced the expression of c-fos in the dorsal raphe serotonin neurons, indicating reduced neural activity. Thus, 2-AR are critical regulators of serotonin neuron excitability.

neuroscience↗

bioRxiv2023

Nucleus Accumbens Local Circuit for Cue-Dependent Aversive Learning

Response to threatening environmental stimuli requires detection and encoding of important environmental features that dictate threat. Aversive events are highly salient which promotes associative learning about stimuli that signal this threat. The nucleus accumbens is uniquely positioned to process this salient, aversive information and promote motivated output, through plasticity on the major projection neurons in the brain area. We uncovered a nucleus accumbens core local circuit whereby excitatory plasticity facilitates learning and recall of discrete aversive cues. We demonstrate that putative nucleus accumbens substance P release and long-term excitatory plasticity on dopamine 2 receptor expressing projection neurons is required for cue-dependent fear learning. Additionally, we found fear learning and recall were dependent on distinct projection-neuron subtypes. Our work demonstrates a critical role for Nucleus Accumbens substance P in cue-dependent aversive learning.

neuroscience↗

bioRxiv2019

Delta glutamate receptor conductance drives excitation of dorsal raphe neurons

The delta glutamate receptors, GluD1R and GluD2R, are mysterious members of the ionotropic glutamate receptor family in that they are not gated by glutamate1,2. One theory is that they are scaffolding proteins or synaptic organizers strictly, rather than ion conducting channels. Although mutant forms and wild type channels have been reported to conduct3,4,5, conduction, gating, and biophysical properties of native GluD1R remain unexplored. Here we show that the inward current induced by activation of 1-adrenergic receptors (1-ARs) in the dorsal raphe nucleus (DR) is mediated by GluD1R. Native GluD1R channels are functional ion channels that are constitutively active under basal conditions and 1-ARs increase the tonic current. This inward current is responsible for the 1-AR-dependent induction of persistent pacemaker-type firing of neurons in the DR. Given the extensive distribution of these receptors, the ionotropic nature of GluDR is proposed to be widespread in the nervous system.

neuroscience↗