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Memory Decoding Journal Club: Behavioral time scale synaptic plasticity underlies CA1 place fields

Behavioral time scale synaptic plasticity underlies CA1 place fields

Neural mechanisms of optimal performance

When we attend a demanding task, our performance is poor at low arousal (when drowsy) or high arousal (when anxious), but we achieve optimal performance at intermediate arousal. This celebrated Yerkes-Dodson inverted-U law relating performance and arousal is colloquially referred to as being "in the zone." In this talk, I will elucidate the behavioral and neural mechanisms linking arousal and performance under the Yerkes-Dodson law in a mouse model. During decision-making tasks, mice express an array of discrete strategies, whereby the optimal strategy occurs at intermediate arousal, measured by pupil, consistent with the inverted-U law. Population recordings from the auditory cortex (A1) further revealed that sound encoding is optimal at intermediate arousal. To explain the computational principle underlying this inverted-U law, we modeled the A1 circuit as a spiking network with excitatory/inhibitory clusters, based on the observed functional clusters in A1. Arousal induced a transition from a multi-attractor (low arousal) to a single attractor phase (high arousal), and performance is optimized at the transition point. The model also predicts stimulus- and arousal-induced modulations of neural variability, which we confirmed in the data. Our theory suggests that a single unifying dynamical principle, phase transitions in metastable dynamics, underlies both the inverted-U law of optimal performance and state-dependent modulations of neural variability.

Decoding ketamine: Neurobiological mechanisms underlying its rapid antidepressant efficacy

Unlike traditional monoamine-based antidepressants that require weeks to exert effects, ketamine alleviates depression within hours, though its clinical use is limited by side effects. While ketamine was initially thought to work primarily through NMDA receptor (NMDAR) inhibition, our research reveals a more complex mechanism. We demonstrate that NMDAR inhibition alone cannot explain ketamine's sustained antidepressant effects, as other NMDAR antagonists like MK-801 lack similar efficacy. Instead, the (2R,6R)-hydroxynorketamine (HNK) metabolite appears critical, exhibiting antidepressant effects without ketamine's side effects. Paradoxically, our findings suggest an inverted U-shaped dose-response relationship where excessive NMDAR inhibition may actually impede antidepressant efficacy, while some level of NMDAR activation is necessary. The antidepressant actions of ketamine and (2R,6R)-HNK require AMPA receptor activation, leading to synaptic potentiation and upregulation of AMPA receptor subunits GluA1 and GluA2. Furthermore, NMDAR subunit GluN2A appears necessary and possibly sufficient for these effects. This research establishes NMDAR-GluN2A activation as a common downstream effector for rapid-acting antidepressants, regardless of their initial targets, offering promising directions for developing next-generation antidepressants with improved efficacy and reduced side effects.

Memory formation in hippocampal microcircuit

The centre of memory is the medial temporal lobe (MTL) and especially the hippocampus. In our research, a more flexible brain-inspired computational microcircuit of the CA1 region of the mammalian hippocampus was upgraded and used to examine how information retrieval could be affected under different conditions. Six models (1-6) were created by modulating different excitatory and inhibitory pathways. The results showed that the increase in the strength of the feedforward excitation was the most effective way to recall memories. In other words, that allows the system to access stored memories more accurately.

Learning produces a hippocampal cognitive map in the form of an orthogonalized state machine

Cognitive maps confer animals with flexible intelligence by representing spatial, temporal, and abstract relationships that can be used to shape thought, planning, and behavior. Cognitive maps have been observed in the hippocampus, but their algorithmic form and the processes by which they are learned remain obscure. Here, we employed large-scale, longitudinal two-photon calcium imaging to record activity from thousands of neurons in the CA1 region of the hippocampus while mice learned to efficiently collect rewards from two subtly different versions of linear tracks in virtual reality. The results provide a detailed view of the formation of a cognitive map in the hippocampus. Throughout learning, both the animal behavior and hippocampal neural activity progressed through multiple intermediate stages, gradually revealing improved task representation that mirrored improved behavioral efficiency. The learning process led to progressive decorrelations in initially similar hippocampal neural activity within and across tracks, ultimately resulting in orthogonalized representations resembling a state machine capturing the inherent struture of the task. We show that a Hidden Markov Model (HMM) and a biologically plausible recurrent neural network trained using Hebbian learning can both capture core aspects of the learning dynamics and the orthogonalized representational structure in neural activity. In contrast, we show that gradient-based learning of sequence models such as Long Short-Term Memory networks (LSTMs) and Transformers do not naturally produce such orthogonalized representations. We further demonstrate that mice exhibited adaptive behavior in novel task settings, with neural activity reflecting flexible deployment of the state machine. These findings shed light on the mathematical form of cognitive maps, the learning rules that sculpt them, and the algorithms that promote adaptive behavior in animals. The work thus charts a course toward a deeper understanding of biological intelligence and offers insights toward developing more robust learning algorithms in artificial intelligence.

Glycolysis regulates neuronal excitability via lactate receptor, HCA1R

Developmentally structured coactivity in the hippocampal trisynaptic loop

The hippocampus is a key player in learning and memory. Research into this brain structure has long emphasized its plasticity and flexibility, though recent reports have come to appreciate its remarkably stable firing patterns. How novel information incorporates itself into networks that maintain their ongoing dynamics remains an open question, largely due to a lack of experimental access points into network stability. Development may provide one such access point. To explore this hypothesis, we birthdated CA1 pyramidal neurons using in-utero electroporation and examined their functional features in freely moving, adult mice. We show that CA1 pyramidal neurons of the same embryonic birthdate exhibit prominent cofiring across different brain states, including behavior in the form of overlapping place fields. Spatial representations remapped across different environments in a manner that preserves the biased correlation patterns between same birthdate neurons. These features of CA1 activity could partially be explained by structured connectivity between pyramidal cells and local interneurons. These observations suggest the existence of developmentally installed circuit motifs that impose powerful constraints on the statistics of hippocampal output.

Hippocampal network dynamics during impaired working memory in epileptic mice

Memory impairment is a common cognitive deficit in temporal lobe epilepsy (TLE). The hippocampus is severely altered in TLE exhibiting multiple anatomical changes that lead to a hyperexcitable network capable of generating frequent epileptic discharges and seizures. In this study we investigated whether hippocampal involvement in epileptic activity drives working memory deficits using bilateral LFP recordings from CA1 during task performance. We discovered that epileptic mice experienced focal rhythmic discharges (FRDs) while they performed the spatial working memory task. Spatial correlation analysis revealed that FRDs were often spatially stable on the maze and were most common around reward zones (25 ‰) and delay zones (50 ‰). Memory performance was correlated with stability of FRDs, suggesting that spatially unstable FRDs interfere with working memory codes in real time.

Flexible selection of task-relevant features through population gating

Brains can gracefully weed out irrelevant stimuli to guide behavior. This feat is believed to rely on a progressive selection of task-relevant stimuli across the cortical hierarchy, but the specific across-area interactions enabling stimulus selection are still unclear. Here, we propose that population gating, occurring within A1 but controlled by top-down inputs from mPFC, can support across-area stimulus selection. Examining single-unit activity recorded while rats performed an auditory context-dependent task, we found that A1 encoded relevant and irrelevant stimuli along a common dimension of its neural space. Yet, the relevant stimulus encoding was enhanced along an extra dimension. In turn, mPFC encoded only the stimulus relevant to the ongoing context. To identify candidate mechanisms for stimulus selection within A1, we reverse-engineered low-rank RNNs trained on a similar task. Our analyses predicted that two context-modulated neural populations gated their preferred stimulus in opposite contexts, which we confirmed in further analyses of A1. Finally, we show in a two-region RNN how population gating within A1 could be controlled by top-down inputs from PFC, enabling flexible across-area communication despite fixed inter-areal connectivity.

From Machine Learning to Autonomous Intelligence

How could machines learn as efficiently as humans and animals? How could machines learn to reason and plan? How could machines learn representations of percepts and action plans at multiple levels of abstraction, enabling them to reason, predict, and plan at multiple time horizons? I will propose a possible path towards autonomous intelligent agents, based on a new modular cognitive architecture and a somewhat new self-supervised training paradigm. The centerpiece of the proposed architecture is a configurable predictive world model that allows the agent to plan. Behavior and learning are driven by a set of differentiable intrinsic cost functions. The world model uses a new type of energy-based model architecture called H-JEPA (Hierarchical Joint Embedding Predictive Architecture). H-JEPA learns hierarchical abstract representations of the world that are simultaneously maximally informative and maximally predictable. The corresponding working paper is available here:https://openreview.net/forum?id=BZ5a1r-kVsf

The functional architecture of the human entorhinal-hippocampal circuitry

Cognitive functions like episodic memory require the formation of cohesive representations. Critical for that process is the entorhinal-hippocampal circuitry’s interaction with cortical information streams and the circuitry’s inner communication. With ultra-high field functional imaging we investigated the functional architecture of the human entorhinal-hippocampal circuitry. We identified an organization that is consistent with convergence of information in anterior and lateral entorhinal subregions and the subiculum/CA1 border while keeping a second route specific for scene processing in a posterior-medial entorhinal subregion and the distal subiculum. Our findings agree with information flow along information processing routes which functionally split the entorhinal-hippocampal circuitry along its transversal axis. My talk will demonstrate how ultra-high field imaging in humans can bridge the gap between anatomical and electrophysiological findings in rodents and our understanding of human cognition. Moreover, I will point out the implications that basic research on functional architecture has for cognitive and clinical research perspectives.

Extrinsic control and intrinsic computation in the hippocampal CA1 network

A key issue in understanding circuit operations is the extent to which neuronal spiking reflects local computation or responses to upstream inputs. Several studies have lesioned or silenced inputs to area CA1 of the hippocampus - either area CA3 or the entorhinal cortex and examined the effect on CA1 pyramidal cells. However, the types of the reported physiological impairments vary widely, primarily because simultaneous manipulations of these redundant inputs have never been performed. In this study, I combined optogenetic silencing of unilateral and bilateral mEC, of the local CA1 region, and performed bilateral pharmacogenetic silencing of CA3. I combined this with high spatial resolution extracellular recordings along the CA1-dentate axis. Silencing the medial entorhinal largely abolished extracellular theta and gamma currents in CA1, without affecting firing rates. In contrast, CA3 and local CA1 silencing strongly decreased firing of CA1 neurons without affecting theta currents. Each perturbation reconfigured the CA1 spatial map. Yet, the ability of the CA1 circuit to support place field activity persisted, maintaining the same fraction of spatially tuned place fields. In contrast to these results, unilateral mEC manipulations that were ineffective in impacting place cells during awake behavior were found to alter sharp-wave ripple sequences activated during sleep. Thus, intrinsic excitatory-inhibitory circuits within CA1 can generate neuronal assemblies in the absence of external inputs, although external synaptic inputs are critical to reconfigure (remap) neuronal assemblies in a brain-state dependent manner.

Elucidating the mechanism underlying Stress and Caffeine-induced motor dysfunction using a mouse model of Episodic Ataxia Type 2

Episodic Ataxia type 2 (EA2), caused by mutations in the CACNA1A gene, results in a loss-of-function of the P/Q type calcium channel, which leads to baseline ataxia, and attacks of dyskinesia, that can last a few hours to a few days. Attacks are brought on by consumption of caffeine, alcohol, and physical or emotional stress. Interestingly, caffeine and stress are common triggers among other episodic channelopathies, as well as causing tremor or shaking in otherwise healthy adults. The mechanism underlying stress and caffeine induced motor impairment remains poorly understood. Utilizing behavior, and in vivo and in vitro electrophysiology in the tottering mouse, a well characterized mouse model of EA2, or WT mice, we first sought to elucidate the mechanism underlying stress-induced motor impairment. We found stress induces attacks in EA2 though the activation of cerebellar alpha 1 adrenergic receptors by norepinephrine (NE) through casein kinase 2 (CK2) dependent phosphorylation. This decreases SK2 channel activity, causing increased Purkinje cell irregularity and motor impairment. Knocking down or blocking CK2 with an FDA approved drug CX-4945 prevented PC irregularity and stress-induced attacks. We next hypothesized caffeine, which has been shown to increase NE levels, could induce attacks through the same alpha 1 adrenergic mechanism in EA2. We found caffeine increases PC irregularity and induces attacks through the same CK2 pathway. Block of alpha 1 adrenergic receptors, however, failed to prevent caffeine-induced attacks. Caffeine instead induces attacks through the block of cerebellar A1 adenosine receptors. This increases the release of glutamate, which interacts with mGluR1 receptors on PC, resulting in erratic firing and motor attacks. Finally, we show a novel direct interaction between mGluR1 and CK2, and inhibition of mGluR1 prior to initiation of attack, prevents the caffeine-induced increase in phosphorylation. These data elucidate the mechanism underlying stress and caffeine-induced motor impairment. Furthermore, given the success of CX-4945 to prevent stress and caffeine induced attacks, it establishes ground-work for the development of therapeutics for the treatment of caffeine and stress induced attacks in EA2 patients and possibly other episodic channelopathies.

Extrinsic control and autonomous computation in the hippocampal CA1 circuit

In understanding circuit operations, a key issue is the extent to which neuronal spiking reflects local computation or responses to upstream inputs. Because pyramidal cells in CA1 do not have local recurrent projections, it is currently assumed that firing in CA1 is inherited from its inputs – thus, entorhinal inputs provide communication with the rest of the neocortex and the outside world, whereas CA3 inputs provide internal and past memory representations. Several studies have attempted to prove this hypothesis, by lesioning or silencing either area CA3 or the entorhinal cortex and examining the effect of firing on CA1 pyramidal cells. Despite the intense and careful work in this research area, the magnitudes and types of the reported physiological impairments vary widely across experiments. At least part of the existing variability and conflicts is due to the different behavioral paradigms, designs and evaluation methods used by different investigators. Simultaneous manipulations in the same animal or even separate manipulations of the different inputs to the hippocampal circuits in the same experiment are rare. To address these issues, I used optogenetic silencing of unilateral and bilateral mEC, of the local CA1 region, and performed bilateral pharmacogenetic silencing of the entire CA3 region. I combined this with high spatial resolution recording of local field potentials (LFP) in the CA1-dentate axis and simultaneously collected firing pattern data from thousands of single neurons. Each experimental animal had up to two of these manipulations being performed simultaneously. Silencing the medial entorhinal (mEC) largely abolished extracellular theta and gamma currents in CA1, without affecting firing rates. In contrast, CA3 and local CA1 silencing strongly decreased firing of CA1 neurons without affecting theta currents. Each perturbation reconfigured the CA1 spatial map. Yet, the ability of the CA1 circuit to support place field activity persisted, maintaining the same fraction of spatially tuned place fields, and reliable assembly expression as in the intact mouse. Thus, the CA1 network can maintain autonomous computation to support coordinated place cell assemblies without reliance on its inputs, yet these inputs can effectively reconfigure and assist in maintaining stability of the CA1 map.

NaV Long-term Inactivation Regulates Adaptation in Place Cells and Depolarization Block in Dopamine Neurons

In behaving rodents, CA1 pyramidal neurons receive spatially-tuned depolarizing synaptic input while traversing a specific location within an environment called its place. Midbrain dopamine neurons participate in reinforcement learning, and bursts of action potentials riding a depolarizing wave of synaptic input signal rewards and reward expectation. Interestingly, slice electrophysiology in vitro shows that both types of cells exhibit a pronounced reduction in firing rate (adaptation) and even cessation of firing during sustained depolarization. We included a five state Markov model of NaV1.6 (for CA1) and NaV1.2 (for dopamine neurons) respectively, in computational models of these two types of neurons. Our simulations suggest that long-term inactivation of this channel is responsible for the adaptation in CA1 pyramidal neurons, in response to triangular depolarizing current ramps. We also show that the differential contribution of slow inactivation in two subpopulations of midbrain dopamine neurons can account for their different dynamic ranges, as assessed by their responses to similar depolarizing ramps. These results suggest long-term inactivation of the sodium channel is a general mechanism for adaptation.

Network mechanisms underlying representational drift in area CA1 of hippocampus

Recent chronic imaging experiments in mice have revealed that the hippocampal code exhibits non-trivial turnover dynamics over long time scales. Specifically, the subset of cells which are active on any given session in a familiar environment changes over the course of days and weeks. While some cells transition into or out of the code after a few sessions, others are stable over the entire experiment. The mechanisms underlying this turnover are unknown. Here we show that the statistics of turnover are consistent with a model in which non-spatial inputs to CA1 pyramidal cells readily undergo plasticity, while spatially tuned inputs are largely stable over time. The heterogeneity in stability across the cell assembly, as well as the decrease in correlation of the population vector of activity over time, are both quantitatively fit by a simple model with Gaussian input statistics. In fact, such input statistics emerge naturally in a network of spiking neurons operating in the fluctuation-driven regime. This correspondence allows one to map the parameters of a large-scale spiking network model of CA1 onto the simple statistical model, and thereby fit the experimental data quantitatively. Importantly, we show that the observed drift is entirely consistent with random, ongoing synaptic turnover. This synaptic turnover is, in turn, consistent with Hebbian plasticity related to continuous learning in a fast memory system.

Norepinephrine links astrocytic activity to regulation of cortical state

Cortical state, defined by the synchrony of population-level neuronal activity, is a key determinant of sensory perception. While many arousal-associated neuromodulators—including norepinephrine (NE)—reduce cortical synchrony, how the cortex resynchronizes following NE signaling remains unknown. Using in vivo two-photon imaging and electrophysiology in mouse visual cortex, we describe a critical role for cortical astrocytes in circuit resynchronization. We characterize astrocytes’ sensitive calcium responses to changes in behavioral arousal and NE, identify that astrocyte signaling precedes increases in cortical synchrony, and demonstrate that astrocyte-specific deletion of Adra1A alters arousal-related cortical synchrony. Our findings demonstrate that astrocytic NE signaling acts as a distinct neuromodulatory pathway, regulating cortical state and linking arousal-associated desynchrony to cortical circuit resynchronization.

The GluN2A Subunit of the NMDA Receptor and Parvalbumin Interneurons: A Possible Role in Interneuron Development

N-methyl-D-aspartate receptors (NMDARs) are excitatory glutamate-gated ion channels that are expressed throughout the central nervous system. NMDARs mediate calcium entry into cells, and are involved in a host of neurological functions. The GluN2A subunit, encoded by the GRIN2A gene, is expressed by both excitatory and inhibitory neurons, with well described roles in pyramidal cells. By using Grin2a knockout mice, we show that the loss of GluN2A signaling impacts parvalbumin-positive (PV) GABAergic interneuron function in hippocampus. Grin2a knockout mice have 33% more PV cells in CA1 compared to wild type but similar cholecystokinin-positive cell density. Immunohistochemistry and electrophysiological recordings show that excess PV cells do eventually incorporate into the hippocampal network and participate in phasic inhibition. Although the morphology of Grin2a knockout PV cells is unaffected, excitability and action-potential firing properties show age-dependent alterations. Preadolescent (P20-25) PV cells have an increased input resistance, longer membrane time constant, longer action-potential half-width, a lower current threshold for depolarization-induced block of action-potential firing, and a decrease in peak action-potential firing rate. Each of these measures are corrected in adulthood, reaching wild type levels, suggesting a potential delay of electrophysiological maturation. The circuit and behavioral implications of this age-dependent PV interneuron malfunction are unknown. However, neonatal Grin2a knockout mice are more susceptible to lipopolysaccharide and febrile-induced seizures, consistent with a critical role for early GluN2A signaling in development and maintenance of excitatory-inhibitory balance. These results could provide insights into how loss-of-function GRIN2A human variants generate an epileptic phenotypes.

NMC4 Short Talk: Novel population of synchronously active pyramidal cells in hippocampal area CA1

Hippocampal pyramidal cells have been widely studied during locomotion, when theta oscillations are present, and during short wave ripples at rest, when replay takes place. However, we find a subset of pyramidal cells that are preferably active during rest, in the absence of theta oscillations and short wave ripples. We recorded these cells using two-photon imaging in dorsal CA1 of the hippocampus of mice, during a virtual reality object location recognition task. During locomotion, the cells show a similar level of activity as control cells, but their activity increases during rest, when this population of cells shows highly synchronous, oscillatory activity at a low frequency (0.1-0.4 Hz). In addition, during both locomotion and rest these cells show place coding, suggesting they may play a role in maintaining a representation of the current location, even when the animal is not moving. We performed simultaneous electrophysiological and calcium recordings, which showed a higher correlation of activity between the LFO and the hippocampal cells in the 0.1-0.4 Hz low frequency band during rest than during locomotion. However, the relationship between the LFO and calcium signals varied between electrodes, suggesting a localized effect. We used the Allen Brain Observatory Neuropixels Visual Coding dataset to further explore this. These data revealed localised low frequency oscillations in CA1 and DG during rest. Overall, we show a novel population of hippocampal cells, and a novel oscillatory band of activity in hippocampus during rest.

Adapt or Die: Transgenerational Inheritance of Pathogen Avoidance (or, How getting food poisoning might save your species)

Caenorhabditis elegans must distinguish pathogens from nutritious food sources among the many bacteria to which it is exposed in its environment1. Here we show that a single exposure to purified small RNAs isolated from pathogenic Pseudomonas aeruginosa (PA14) is sufficient to induce pathogen avoidance in the treated worms and in four subsequent generations of progeny. The RNA interference (RNAi) and PIWI-interacting RNA (piRNA) pathways, the germline and the ASI neuron are all required for avoidance behaviour induced by bacterial small RNAs, and for the transgenerational inheritance of this behaviour. A single P. aeruginosa non-coding RNA, P11, is both necessary and sufficient to convey learned avoidance of PA14, and its C. elegans target, maco-1, is required for avoidance. Our results suggest that this non-coding-RNA-dependent mechanism evolved to survey the microbial environment of the worm, use this information to make appropriate behavioural decisions and pass this information on to its progeny.

Nr4a1 and chromatin bivalency in cocaine pathophysiology

Mechanisms of CACNA1A-associated developmental epileptic encephalopathies

Developmental epileptic encephalopathies are early-onset epilepsies, often refractory to therapy, with developmental delay or regression. These disorders carry poor neurodevelopmental prognosis, with long-term refractory epilepsy and persistent cognitive, behavioral and motor deficits. Mutations in the CACNA1A gene, encoding the pore-forming α1 subunit of CaV2.1 voltage-gated calcium channels, result in a spectrum of neurological disorders, including severe, early-onset epileptic encephalopathies. Recent work from the Rossignol lab helped characterize the phenotypic spectrum of CACNA1A-related epilepsies in humans. Using conditional genetics and novel animal models, the Rossignol lab unveiled some of the underlying pathophysiological mechanisms, including critical deficits in cortical inhibition, resulting in seizures and a range of cognitive-behavioral deficits. Importantly, Dr. Rossignol’s team demonstrated that the targeted activation of specific GABAergic interneuron populations in selected cortical regions prevents motor seizures and reverts attention deficits and cognitive rigidity in mouse models of the disorder. These recent findings open novel avenues for the treatment of these severe CACNA1A-associated neurodevelopmental disorders.

Evidence for the role of glymphatic dysfunction in the development of Alzheimer’s disease

Glymphatic perivascular exchange is supported by the astroglial water channel aquaporin-4 (AQP4), which localizes to perivascular astrocytic endfeet surrounding the cerebral vasculature. In aging mice, impairment of glymphatic function is associated with reduced perivascular AQP4 localization, yet whether these changes contribute to the development of neurodegenerative disease, such as Alzheimer’s disease (AD), remains unknown. Using post mortem human tissue, we evaluated perivascular AQP4 localization in the frontal cortical gray matter, white matter, and hippocampus of cognitively normal subjects and those with AD. Loss of perivascular and increasing cellular localization of AQP4 in the frontal gray matter was specifically associated with AD status, amyloid β (Aβ) and tau pathology, and cognitive decline in the early stages of disease. Using AAV-PHP.B to drive expression on non-perivascular AQP4 in wild type and Tg2576 (APPSwe, mouse model of Aβ deposition) mice, increased cellular AQP4 localization did not slow glymphatic function or change Aβ deposition. Using the Snta1 knockout line (which lacks perivascular AQP4 localization), we observed that loss AQP4 from perivascular endfeet slowed glymphatic function in wild type mice and accelerated Aβ plaque deposition in Tg2576 mice. These findings demonstrate that loss of perivascular AQP4 localization, and not increased cellular AQP4 localization, slows glymphatic function and promotes the development of AD pathology. To evaluate whether naturally occurring variation in the human AQP4 gene, or the alpha syntrophin (SNTA1), dystrobrevin (DTNA) or dystroglycan (DAG1) genes (whose products maintain perivascular AQP4 localization) confer risk for or protection from AD pathology or clinical progression, we evaluated 56 tag single nucleotide polymorphisms (SNPs) across these genes for association with CSF AD biomarkers, MRI measures of cortical and hippocampal atrophy, and longitudinal cognitive decline in the Alzheimer’s Disease Neuroimaging Initiative I (ADNI I) cohort. We identify 25 different significant associations between AQP4, SNTA1, DTNA, and DAG1 tag SNPs and phenotypic measures of AD pathology and progression. These findings provide complimentary human genetic evidence for the contribution of perivascular glymphatic dysfunction to the development of AD in human populations.

Disinhibitory and neuromodulatory regulation of hippocampal synaptic plasticity

The CA1 pyramidal neurons are embedded in an intricate local circuitry that contains a variety of interneurons. The roles these interneurons play in the regulation of the excitatory synaptic plasticity remains largely understudied. Recent experiments showed that repeated cholinergic activation of 𝛼7 nACh receptors expressed in oriens-lacunosum-moleculare (OLM𝛼2) interneurons could induce LTP in SC-CA1 synapses. We used a biophysically realistic computational model to examine mechanistically how cholinergic activation of OLMa2 interneurons increases SC to CA1 transmission. Our results suggest that, when properly timed, activation of OLMa2 interneurons cancels the feedforward inhibition onto CA1 pyramidal cells by inhibiting fast-spiking interneurons that synapse on the same dendritic compartment as the SC, i.e., by disinhibiting the pyramidal cell dendritic compartment. Our work further describes the pairing of disinhibition with SC stimulation as a general mechanism for the induction of synaptic plasticity. We found that locally-reduced GABA release (disinhibition) paired with SC stimulation could lead to increased NMDAR activation and intracellular calcium concentration sufficient to upregulate AMPAR permeability and potentiate the excitatory synapse. Our work suggests that inhibitory synapses critically modulate excitatory neurotransmission and induction of plasticity at excitatory synapses. Our work also shows how cholinergic action on OLM interneurons, a mechanism whose disruption is associated with memory impairment, can down-regulate the GABAergic signaling into CA1 pyramidal cells and facilitate potentiation of the SC-CA1 synapse.

Acetylcholine modulation of short-term plasticity is critical to reliable long-term plasticity in hippocampal synapses

CA3-CA1 synapses in the hippocampus are the initial locus of episodic memory. The action of acetylcholine alters cellular excitability, modifies neuronal networks, and triggers secondary signaling that directly affects long-term plasticity (LTP) (the cellular underpinning of memory). It is therefore considered a critical regulator of learning and memory in the brain. Its action via M4 metabotropic receptors in the presynaptic terminal of the CA3 neurons and M1 metabotropic receptors in the postsynaptic spines of CA1 neurons produce rich dynamics across multiple timescales. We developed a model to describe the activation of postsynaptic M1 receptors that leads to IP3 production from membrane PIP2 molecules. The binding of IP3 to IP3 receptors in the endoplasmic reticulum (ER) ultimately causes calcium release. This calcium release from the ER activates potassium channels like the calcium-activated SK channels and alters different aspects of synaptic signaling. In an independent signaling cascade, M1 receptors also directly suppress SK channels and the voltage-activated KCNQ2/3 channels, enhancing post-synaptic excitability. In the CA3 presynaptic terminal, we model the reduction of the voltage sensitivity of voltage-gated calcium channels (VGCCs) and the resulting suppression of neurotransmitter release by the action of the M4 receptors. Our results show that the reduced initial release probability because of acetylcholine alters short-term plasticity (STP) dynamics. We characterize the dichotomy of suppressing neurotransmitter release from CA3 neurons and the enhanced excitability of the postsynaptic CA1 spine. Mechanisms underlying STP operate over a few seconds, while those responsible for LTP last for hours, and both forms of plasticity have been linked with very distinct functions in the brain. We show that the concurrent suppression of neurotransmitter release and increased sensitivity conserves neurotransmitter vesicles and enhances the reliability in plasticity. Our work establishes a relationship between STP and LTP coordinated by neuromodulation with acetylcholine.

Sleepless in Vienna - how to rescue folding-deficient dopamine transporters by pharmacochaperoning

Diseases that arise from misfolding of an individual protein are rare. However, collectively, these folding diseases represent a large proportion of hereditary and acquired disorders. In fact, the term "Molecular Medicine" was coined by Linus Pauling in conjunction with the study of a folding disease, i.e. sickle cell anemia. In the past decade, we have witnessed an exponential growth in the number of mutations, which have been identified in genes encoding solute carriers (SLC). A sizable faction - presumably the majority - of these mutations result in misfolding of the encoded protein. While studying the export of the GABA transporter (SLC6A1) and of the serotonin transporter (SLC6A4), from the endoplasmic reticulum (ER), we discovered by serendipity that some ligands can correct the folding defect imparted by point mutations. These bind to the inward facing state. The most effective compound is noribogaine, the metabolite of ibogaine (an alkaloid first isolated from the shrub Tabernanthe iboga). There are 13 mutations in the human dopamine transporter (DAT, SLC6A3), which give rise to a syndrome of infantile Parkinsonism and dystonia. We capitalized on our insights to explore, if the disease-relevant mutant proteins were amenable to pharmacological correction. Drosopohila melanogaster, which lack the dopamine transporter, are hyperactive and sleepless (fumin in Japanese). Thus, mutated human DAT variants can be introduced into fumin flies. This allows for examining the effect of pharmacochaperones on delivery of DAT to the axonal territory and on restoring sleep. We explored the chemical space populated by variations of the ibogaine structure to identify an analogue (referred to as compound 9b), which was highly effective: compound 9b also restored folding in DAT variants, which were not amenable to rescue by noribogaine. Deficiencies in the human creatine transporter-1 (CrT1, SLC6A8) give rise to a syndrome of intellectual disability and seizures and accounts for 5% of genetically based intellectual disabilities in boys. Point mutations occur, in part, at positions, which are homologous to those of folding-deficient DAT variants. CrT1 lacks the rich pharmacology of monoamine transporters. Nevertheless, our insights are also applicable to rescuing some disease-related variants of CrT1. Finally, the question arises how one can address the folding problem. We propose a two-pronged approach: (i) analyzing the effect of mutations on the transport cycle by electrophysiological recordings; this allows for extracting information on the rates of conformational transitions. The underlying assumption posits that - even when remedied by pharmacochaperoning - folding-deficient mutants must differ in the conformational transitions associated with the transport cycle. (ii) analyzing the effect of mutations on the two components of protein stability, i.e. thermodynamic and kinetic stability. This is expected to provide a glimpse of the energy landscape, which governs the folding trajectory.

Natural switches in sensory attention rapidly modulate hippocampal spatial codes

During natural behavior animals dynamically switch between different behaviors, yet little is known about how the brain performs behavioral-switches. Navigation is a complex dynamic behavior that enables testing these kind of behavioral switches: It requires the animal to know its own allocentric (world-centered) location within the environment, while also paying attention to incoming sudden events such as obstacles or other conspecifics – and therefore the animal may need to rapidly switch from representing its own allocentric position to egocentrically representing ‘things out-there’. Here we used an ethological task where two bats flew together in a very large environment (130 meters), and had to switch between two behaviors: (i) navigation, and (ii) obstacle-avoidance during ‘cross-over’ events with the other bat. Bats increased their echolocation click-rate before a cross-over, indicating spatial attention to the other bat. Hippocampal CA1 neurons represented the bat’s own position when flying alone (allocentric place-coding); surprisingly, when meeting the other bat, neurons switched very rapidly to jointly representing the inter-bat distance × position (egocentric × allocentric coding). This switching to a neuronal representation of the other bat was correlated on a trial-by-trial basis with the attention signal, as indexed by the bat’s echolocation calls – suggesting that sensory attention is controlling these major switches in neural coding. Interestingly, we found that in place-cells, the different place-fields of the same neuron could exhibit very different tuning to inter-bat distance – creating a non-separable coding of allocentric position × egocentric distance. Together, our results suggest that attentional switches during navigation – which in bats can be measured directly based on their echolocation signals – elicit rapid dynamics of hippocampal spatial coding. More broadly, this study demonstrates that during natural behavior, when animals often switch between different behaviors, neural circuits can rapidly and flexibly switch their core computations.

Meta-analytic evidence of differential prefrontal and early sensory cortex activity during non-social sensory perception in autism

To date, neuroimaging research has had a limited focus on non-social features of autism. As a result, neurobiological explanations for atypical sensory perception in autism are lacking. To address this, we quantitively condensed findings from the non-social autism fMRI literature in line with the current best practices for neuroimaging meta-analyses. Using activation likelihood estimation (ALE), we conducted a series of robust meta-analyses across 83 experiments from 52 fMRI studies investigating differences between autistic (n = 891) and typical (n = 967) participants. We found that typical controls, compared to autistic people, show greater activity in the prefrontal cortex (BA9, BA10) during perception tasks. More refined analyses revealed that, when compared to typical controls, autistic people show greater recruitment of the extrastriate V2 cortex (BA18) during visual processing. Taken together, these findings contribute to our understanding of current theories of autistic perception, and highlight some of the challenges of cognitive neuroscience research in autism.

Spatiotemporal patterns of neocortical activity around hippocampal sharp-wave ripples

Neocortical-hippocampal interactions during off-line periods such as slow-wave sleep are implicated in memory processing. In particular, recent memory traces are replayed in hippocampus during some sharp-wave ripple (SWR) events, and these replay events are positively correlated with neocortical memory trace reactivation. A prevalent model is that SWR arise ‘spontaneously’ in CA3 and propagate recent memory ‘indices’ outward to the neocortex to enable memory consolidation there; however, the spatiotemporal distribution of neocortical activation relative to SWR is incompletely understood. We used wide-field optical imaging to study voltage and glutamate release transients in dorsal neocortex in relation to CA1 multiunit activity (MUA) and SWR of sleeping and urethane anesthetized mice. Modulation of voltage and glutamate release signals in relation to SWRs varied across superficial neocortical regions, and it was largest in posteromedial regions surrounding retrosplenial cortex (RSC), which receives strong hippocampal output connections. Activity tended to spread sequentially from more medial towards more lateral regions. Contrary to the unidirectional hypothesis, activation exhibited a continuum of timing relative to SWRs, varying from neocortex leading to neocortex lagging the SWRs (± ~250 msec). The timing continuum was correlated with the skewness of peri-SWR hippocampal MUA and with a tendency for some SWR to occur in clusters. Thus, contrary to the model in which SWRs arise spontaneously in hippocampus, neocortical activation often precedes SWRs and may thus constitute a trigger event in which neocortical information seeds associative reactivation of hippocampal ‘indices’.

Nr4a1-mediated morphological adaptations in Ventral Pallidal projections to Mediodorsal Thalamus support cocaine intake and relapse-like behaviors

Growing evidence suggests the ventral pallidum (VP) is critical for drug intake and seeking behaviors. Receiving dense projections from the nucleus accumbens as well as dopamine inputs from the midbrain, the VP plays a central role in the control of motivated behaviors. Repeated exposure to cocaine is known to alter VP neuronal firing and neurotransmission. Surprisingly, there is limited information on the molecular adaptations occurring in VP neurons following cocaine intake.To provide insights into cocaine-induced transcriptional alterations we performed RNA-sequencing on VP of mice following cocaine self-administration. Gene Ontology analysis pointed toward alterations in dendrite- and spinerelated genes. Subsequent transcriptional regulator analysis identified the transcription factor Nr4a1 as a common regulator for these sets of morphology-related genes.Consistent with the central role of the VP in reward, its neurons project to several key regions associated with cocaine-mediated behaviors. We thus assessed Nr4a1 expression levels in various projection populations.Following cocaine self-administration, VP neurons projecting to the mediodorsal thalamus (MDT) showed significantly increased Nr4a1 levels. To further investigate the role of Nr4a1 in cocaine intake and relapse, we bidirectionally manipulated its expression levels selectively in VP neurons projecting to the MDT. Increasing Nr4a1 levels resulted in enhanced relapse-like behaviors accompanied by a blockage of cocaine-induced spinogenesis.However, decreasing Nr4a1expression levels completely abolished cocaine intake and consequential relapse-like behaviors. Together, our preliminary findings suggest that drug-induced neuronal remodeling in pallido-thalamic circuits is critical for cocaine intake and relapse-like behaviors.

Interneuron desynchronization and breakdown of long-term place cell stability in temporal lobe epilepsy

Temporal lobe epilepsy is associated with memory deficits but the circuit mechanisms underlying these cognitive disabilities are not understood. We used electrophysiological recordings, open-source wire-free miniaturized microscopy and computational modeling to probe these deficits in a model of temporal lobe epilepsy. We find desynchronization of dentate gyrus interneurons with CA1 interneurons during theta oscillations and a loss of precision and stability of place fields. We also find that emergence of place cell dysfunction is delayed, providing a potential temporal window for treatments. Computation modeling shows that desynchronization rather than interneuron cell loss can drive place cell dysfunction. Future studies will uncover cell types driving these changes and transcriptional changes that may be driving dysfunction.

Using evolutionary algorithms to explore single-cell heterogeneity and microcircuit operation in the hippocampus

The hippocampus-entorhinal system is critical for learning and memory. Recent cutting-edge single-cell technologies from RNAseq to electrophysiology are disclosing a so far unrecognized heterogeneity within the major cell types (1). Surprisingly, massive high-throughput recordings of these very same cells identify low dimensional microcircuit dynamics (2,3). Reconciling both views is critical to understand how the brain operates. " "The CA1 region is considered high in the hierarchy of the entorhinal-hippocampal system. Traditionally viewed as a single layered structure, recent evidence has disclosed an exquisite laminar organization across deep and superficial pyramidal sublayers at the transcriptional, morphological and functional levels (1,4,5). Such a low-dimensional segregation may be driven by a combination of intrinsic, biophysical and microcircuit factors but mechanisms are unknown." "Here, we exploit evolutionary algorithms to address the effect of single-cell heterogeneity on CA1 pyramidal cell activity (6). First, we developed a biophysically realistic model of CA1 pyramidal cells using the Hodgkin-Huxley multi-compartment formalism in the Neuron+Python platform and the morphological database Neuromorpho.org. We adopted genetic algorithms (GA) to identify passive, active and synaptic conductances resulting in realistic electrophysiological behavior. We then used the generated models to explore the functional effect of intrinsic, synaptic and morphological heterogeneity during oscillatory activities. By combining results from all simulations in a logistic regression model we evaluated the effect of up/down-regulation of different factors. We found that muyltidimensional excitatory and inhibitory inputs interact with morphological and intrinsic factors to determine a low dimensional subset of output features (e.g. phase-locking preference) that matches non-fitted experimental data.

Neural coding in the auditory cortex - "Emergent Scientists Seminar Series

Dr Jennifer Lawlor Title: Tracking changes in complex auditory scenes along the cortical pathway Complex acoustic environments, such as a busy street, are characterised by their everchanging dynamics. Despite their complexity, listeners can readily tease apart relevant changes from irrelevant variations. This requires continuously tracking the appropriate sensory evidence while discarding noisy acoustic variations. Despite the apparent simplicity of this perceptual phenomenon, the neural basis of the extraction of relevant information in complex continuous streams for goal-directed behavior is currently not well understood. As a minimalistic model for change detection in complex auditory environments, we designed broad-range tone clouds whose first-order statistics change at a random time. Subjects (humans or ferrets) were trained to detect these changes.They were faced with the dual-task of estimating the baseline statistics and detecting a potential change in those statistics at any moment. To characterize the extraction and encoding of relevant sensory information along the cortical hierarchy, we first recorded the brain electrical activity of human subjects engaged in this task using electroencephalography. Human performance and reaction times improved with longer pre-change exposure, consistent with improved estimation of baseline statistics. Change-locked and decision-related EEG responses were found in a centro-parietal scalp location, whose slope depended on change size, consistent with sensory evidence accumulation. To further this investigation, we performed a series of electrophysiological recordings in the primary auditory cortex (A1), secondary auditory cortex (PEG) and frontal cortex (FC) of the fully trained behaving ferret. A1 neurons exhibited strong onset responses and change-related discharges specific to neuronal tuning. PEG population showed reduced onset-related responses, but more categorical change-related modulations. Finally, a subset of FC neurons (dlPFC/premotor) presented a generalized response to all change-related events only during behavior. We show using a Generalized Linear Model (GLM) that the same subpopulation in FC encodes sensory and decision signals, suggesting that FC neurons could operate conversion of sensory evidence to perceptual decision. All together, these area-specific responses suggest a behavior-dependent mechanism of sensory extraction and generalization of task-relevant event. Aleksandar Ivanov Title: How does the auditory system adapt to different environments: A song of echoes and adaptation

Modeling HCN Channel-Mediated Modulation on Dendro-Somatic Electric Coupling in CA1 Pyramidal Cells

Bernstein Conference 2024

Comparable theta phase coding dynamics along the CA1 transverse axis

COSYNE 2022

The role of hippocampal CA1 in relational learning in mice

COSYNE 2022

The role of hippocampal CA1 in relational learning in mice

COSYNE 2022

Direct cortical inputs to hippocampal area CA1 transmit complementary signals for goal-directed navigation

COSYNE 2023

Mechanisms of contextual fear memory suppression and extinction by the Nucleus Reuniens-CA1 pathway

COSYNE 2023

Place Cells are Clustered by Field Location in CA1 Hippocampus

COSYNE 2023

Reduced correlations in spontaneous activity amongst CA1 engram cells

COSYNE 2023

A role for hippocampal CA1 in structural learning in mice

COSYNE 2023

The accumulation of dendritic extracellular Potassium as in vivo model of epilepsy in CA1 pyramidal neurons

COSYNE 2025

A role for hippocampal CA1 in structural learning in mice

COSYNE 2025

Activity dynamics of hippocampal CA1 pyramidal neurons during virtual navigation in mice

Amyloid beta impairs synaptic plasticity at the hippocampal CA3-CA1 synapses in Alzheimer’s disease: a computational modeling study

An antiseizure adenosine A1R agonist inhibits hippocampal synaptic transmission in epileptic rats but not in control ones

Astrocyte-neuron interplay is critical for Alzheimer's disease pathogenesis and is rescued by TRPA1 channel blockade

Behavioral responses evoked by optogenetic activation of Cacna1h-expressing low threshold mechanoreceptors in mice

Capturing dynamics of inhibitory synaptic connectivity underlying learning using in vivo two-photon optical imaging of hippocampal CA1

Contribution of GBA1 mutations to autophagy-lysosomal pathway in Parkinson's disease

CYP46A1 in the choroid plexus: an unexpected safeguard of brain function lost in Alzheimer’s disease

Differential Regulation of CREB and AKT by cyclic AMP in the developing retina: The role of A1 adenosine receptors

Differential value and outcome processing between dorsal and ventral CA1 regions of the hippocampus

Distinct hippocampal network states support theta phase precession and theta sequences in CA1

A distributed population code for object representation in CA1 of the hippocampus

Dopamine D2-Like Receptors Bidirectionally Regulate CA1 Synaptic Plasticity and Modulate Cumulative Spatial Memory in Rats

Dysregulation of CA1 hippocampal activity across the sleep-wake cycle in Alzheimer’s disease mouse model

Early impaired CA3-CA1 synapses in an APP knock-in mice model of Alzheimer's disease

Electrophysiological characteristics of human induced pluripotent stem cell-derived neurons with CACNA1A variants

The event timing-dependent plasticity rule corroborates the key role of dendritic spikes for LTP induction at distal apical synapses in the CA1 pyramidal cell model

Experience-dependent reorganization of hippocampal CA1 pyramidal cell representations in a virtual contextual go-no go task

Exploring the impact of excitation-inhibition balance through synaptic placement in a biophysical model of CA1 pyramidal cell

Expression of c-Fos in the vCA1, dCA2, chemosensory amygdala and reward system of female mice induced by male pheromonal signals

Functional characterization of a novel dual A2A/A2B adenosine receptor antagonist on CA1 synaptic plasticity or during oxygen glucose deprivation

FUSDelta14 mutation impairs normal neuronal development and causes systemic lipid metabolic alterations

GABAergic Mechanisms of Localized Fast Neuronal Oscillations in the Mouse Hippocampal CA1 Area During Active Exploration

GBA1 inactivation in oligodendrocytes affects myelination and induces neurodegeneration and lipid dyshomeostasis in mice

The geometry of object representations in CA1 ensembles during spontaneous exploration

Glucocerebrosidase (GCase) translocation to lysosomes and GCase level in primary macrophages derived from GBA1 mutation carriers with and without Parkinson's disease

Glycine Transporter Inhibitor 1 Rescues Excitatory/Inhibitory Imbalance Mediated by GluA1 AMPA Receptor Ablation from Parvalbumin-Positive Interneurons

Homeostatic regulation of CA1 firing rate set points in response to chronic hyperactivation of interneurons

Computational analysis of optogenetic inhibition of a pyramidal CA1 neuron

Bernstein Conference 2024