bioRxiv Subject Collection: Neuroscience's Journal
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Saturday, January 27th, 2024
| Time |
Event |
| 12:16a |
Vagus nerve stimulation (VNS) modulates synaptic plasticity in the rat infralimbic cortex via Trk-B receptor activation to reduce drug-seeking
Drugs of abuse cause changes in the prefrontal cortex (PFC) and associated regions that impair inhibitory control over drug-seeking. Breaking the contingencies between drug-associated cues and the delivery of the reward during extinction learning reduces relapse. Vagus nerve stimulation (VNS) has previously been shown to enhance extinction learning and reduce drug-seeking. Here we determined the effects of VNS-mediated release of brain-derived neurotrophic factor (BDNF) on extinction and cue-induced reinstatement in rats trained to self-administer cocaine. Pairing 10 days of extinction training with VNS facilitated extinction and reduced drug-seeking behavior during reinstatement. Rats that received a single extinction session with VNS showed elevated BDNF levels in the medial PFC as determined via an enzyme-linked immunosorbent assay (ELISA). Systemic blockade of Tropomyosin receptor kinase B (TrkB) receptors during extinction, via the TrkB antagonist ANA-12, decreased the effects of VNS on extinction and reinstatement. Whole-cell recordings in brain slices showed that cocaine self-administration induced alterations in the ratio of AMPA and NMDA receptor-mediated currents in layer 5 pyramidal neurons of the infralimbic cortex (IL). Pairing extinction with VNS reversed cocaine-induced changes in glutamatergic transmission by enhancing AMPAR currents, and this effect was blocked by ANA-12. Our study suggests that VNS consolidates extinction of drug-seeking behavior by reversing drug-induced changes in synaptic AMPA receptors in the IL, and this effect is abolished by blocking TrkB receptors during extinction, highlighting a potential mechanism for the therapeutic effects of VNS in addiction. | | 1:01a |
Differential encoding of fear learning and fear expression in the ventral and dorsal hippocampus
While there is substantial evidence that the dorsal and ventral hippocampus play different roles during emotional learning, it is unknown how these roles are implemented. Here, we simultaneously recorded in these structures during fear conditioning, and demonstrated a predominance of responses related to fear expression in dorsal hippocampus, while ventral hippocampal responses were more closely linked with the acquisition of conditioned fear. Furthermore, cell assemblies containing both dorsal and ventral neurons emerged during fear conditioning, therefore suggesting a potential substrate to integrate these complementary signals for learning and behavior. | | 11:32a |
Inferring neural dynamics of memory during naturalistic social communication
Memory processes in complex behaviors like social communication require forming representations of the past that grow with time. The neural mechanisms that support such continually growing memory remain unknown. We address this gap in the context of fly courtship, a natural social behavior involving the production and perception of long, complex song sequences. To study female memory for male song history in unrestrained courtship, we present "Natural Continuation" (NC)---a general, simulation-based model comparison procedure to evaluate candidate neural codes for complex stimuli using naturalistic behavioral data. Applying NC to fly courtship revealed strong evidence for an adaptive population mechanism for how female auditory neural dynamics could convert long song histories into a rich mnemonic format. Song temporal patterning is continually transformed by heterogeneous nonlinear adaptation dynamics, then integrated into persistent activity, enabling common neural mechanisms to retain continuously unfolding information over long periods and yielding state-of-the-art predictions of female courtship behavior. At a population level this coding model produces multi-dimensional advection-diffusion-like responses that separate songs over a continuum of timescales and can be linearly transformed into flexible output signals, illustrating its potential to create a generic, scalable mnemonic format for extended input signals poised to drive complex behavioral responses. This work thus shows how naturalistic behavior can directly inform neural population coding models, revealing here a novel process for memory formation. | | 11:32a |
Metabotropic NMDA Receptor Signaling Contributes to Sex Differences in Synaptic Plasticity and Episodic Memory
Men generally outperform women on encoding spatial components of episodic memory whereas the reverse holds for semantic elements. Here we show that female mice outperform males on tests for non-spatial aspects of episodic memory ("what", "when"), suggesting that the human findings are influenced by neurobiological factors common to mammals. Analysis of hippocampal synaptic plasticity mechanisms and encoding revealed unprecedented, sex-specific contributions of non-classical metabotropic NMDA receptor (NMDAR) functions. While both sexes used non-ionic NMDAR signaling to trigger actin polymerization needed to consolidate long-term potentiation (LTP), NMDAR GluN2B subunit antagonism blocked these effects in males only and had the corresponding sex-specific effect on episodic memory. Conversely, blocking estrogen receptor alpha eliminated metabotropic stabilization of LTP and episodic memory in females only. The results show that sex differences in metabotropic signaling critical for enduring synaptic plasticity in hippocampus have significant consequences for encoding episodic memories. | | 11:32a |
The Neural Basis of Event Segmentation:Stable Features in the Environment areReflected by Neural States
Our senses receive a continuous stream of complex information. Parsing this information into meaningful events allows us to extract relevant information, remember it, and act upon it. Previous research has related these events to so-called ''neural states'': temporally and regionally specific stable patterns of brain activity, which tend to coincide with events in the stimulus. Neural states show a temporal cortical hierarchy: short states are present in early sensory areas, while longer states can be found in higher-level areas. Here we investigated what these neural states represent. We hypothesized that states at different levels of the cortical hierarchy are shaped by aspects of the stimulus to which these brain areas are responsive. To test this hypothesis, we analyzed fMRI data of participants watching a movie, using a data-driven method to identify the neural states. We found support for the aforementioned hypothesis: specifically the parahippocampal place area and retrosplenial cortex, known to be sensitive to places, showed an alignment between neural state boundaries and moments in the movie with a change in location, independent of changes in visual features. These findings suggest that neural states reflect stable features in the (internal model of) the external environment, and that the cortical temporal hierarchy partly reflects the temporal scales at which representations of the environment evolve. | | 6:19p |
Early dynamics of excitation and inhibition maintain late frequency tuning in auditory cortex
In the auditory cortex the onset of a tone evokes time-varying excitation and inhibition. However, the role of early inhibition in shaping the temporal properties of tone-evoked responses has not been fully characterized. By using Archaerhodopsin-3 (Arch) to photo-suppress the activity of the parvalbumin-expressing (PV) class of inhibitory interneurons, we manipulated the early component of tone-evoked inhibition. We find that early inhibition directly controls the output gain of the response, reducing the number of spikes proportionately across all frequencies. However, by controlling early activity, transient inhibition prevents late excitation and spiking for non-optimal frequencies. Thus, transient tone-evoked inhibition plays a critical long-lasting role in shaping response properties in the auditory cortex. | | 7:30p |
Hyper-Flexible Neural Networks: Rapidly Switching between Logic Operations in a Compact 4-Neuron Circuit
Neural networks of various levels exhibit rapid adaptability to diverse environmental stimuli. Such fast response times imply that adaptation cannot rely solely on synaptic plasticity, which operates on a much slower timescale. Instead, circuits must be inherently hyper-flexible and receptive to switches in functionalities. In this study, we show that a 4-neuron circuit can rapidly and controllably switch between 24 unique functions, while maintaining the same set of synaptic weights. Specifically, in order to systematically classify the outputs relative to inputs, we classify unique types of information processing in terms of 8 non-trivial logical truth tables (AND, OR, XOR, etc.). Furthermore, we test 3 different classes of input characteristics, difference in magnitude, timing and phase between input signals, and show that this small circuit can switch between different computations simply by adjusting its bias current. Finally, we demonstrate that this flexibility can be used to reduce the traditional nine gate adder into two 4-neuron circuits. This provides a computational foundation for how neural adaptability can occur on timescales much shorter than plasticity, an aspect important yet less explored in previous literature. This is a novel way to control a neural circuit, and could lead to new types of computing, especially in the growing field of neuromorphic computing. | | 7:30p |
LOCAL SPATIAL FLOWS AND PROPAGATIVE ATTRACTORS: A NOVEL 'FLOWNECTOME' FRAMEWORK FOR ANALYZING BOLD FMRI DYNAMICS
Although the analysis of temporal signal fluctuations and co-fluctuations has long been a fixture of blood oxygenation-level dependent (BOLD) functional magnetic resonance imaging (fMRI) research, the role of local directional flows in both signal propagation and healthy functional integration remains almost entirely neglected. We are introducing an extensible framework, based on localized directional signal flows, to capture and analyze spatial signal propagation and propagative attractor patterns in BOLD fMRI. Novel features derived from this approach are validated in a large resting-state fMRI schizophrenia study where they reveal significant relationships between spatially directional flows, propagative attractor patterns and subject diagnostic status. Plausibly, we find that spatial signal inflow to functional regions tends to positively correlate with net gain/loss in the region's temporal contribution BOLD signal reconstruction. We also find that group ICA (pdGICA) performed on time-varying propagative density maps, which are whole-brain maps of spatial signal inflow to each voxel on successive 30 second windows (ie. propagative attractor maps), produce components that tend to concentrate predominantly in at most six or seven functional regions, in some cases focusing on as few as two. The relationship between the propagative attractor group ICA component maps and functional regions is not sharp, but is focused enough to render the pdGICA component maps functionally tractable. Temporal correlations between pdGICA component timeseries and net gain/loss functional region timeseries on corresponding windows echoes those traditionally observed between functional region timeseries when aligning each pdGICA component with the functional region with which it has greatest spatial overlap. Schizophrenia strongly disrupts the average correlative relationship between pdGICA components and certain functional regions, some of which tend to be implicated in schizophrenia e.g. the thalamus and the anterior cingulate cortex. Schizophrenia also strongly and pervasively linked to the importance of specific pdGICA components in reconstructing subjects' observed time-varying propagative density maps. Over half of the 35 pdGICA component make significantly different average contributions to patient propagative density maps than to those of controls, with the functional footprints of impacted pdGICA components spreading over diverse functional domains. Finally, the magnitudes of local directional flows that carry propagation have spatially structured averages and structured, pervasive schizophrenia effects. The framework introduced here follows a new and fundamentally different data-driven approach to the BOLD fMRI signal. We believe that the empirical measurement of local directional flows and wider spatial signal propagation opens a plethora of new avenues through which to investigate healthy and disordered brain function using BOLD fMRI. | | 7:30p |
Zebrafish live imaging reveals only around 2% rather than 50% of motor neurons die through apoptosis during development
It is widely accepted that neurons will die through apoptosis if they cannot receive enough growth factors during development of vertebrates; however, there is still no real-time observation showing this dying process in live animals. Here, we generated sensor zebrafish achieving live imaging of motor neuron apoptosis at single-cell resolution. Using these sensor zebrafish, we observed for the first time that in an apoptotic motor neuron, caspase-3 activation occurred quickly within 5-6 min and at the same time between the cell body and axon. Interestingly, we found that only around 2% of motor neurons died during zebrafish development, which is much lower than the generally believed 50% cell death occurred in embryonic stage of vertebrates. Our data also showed that most of the apoptotic bodies of these dead motor neurons were not cleared by macrophages. These sensor zebrafish can serve as powerful tools to study motor neuron apoptosis in vivo. | | 7:30p |
From Nutritional Patterns to Behavior: High-Fat Diet Influences on Inhibitory Control, Brain Gene Expression and Metabolomics in Rats
Background: Impulsive and compulsive behaviors are associated with inhibitory control deficits. Diet plays a pivotal role in normal development, impacting both physiology and behavior. However, the specific effects of high-fat diets (HFD) on inhibitory control have not received adequate attention. Objectives: This study aimed to explore how exposure to an HFD from postnatal day (PND) 33 to PND77 affects impulsive and compulsive behaviors. Methods: The experiment involved 40 Wistar rats, half of which were male and subjected to the HFD or Chow diets. Several tasks were employed to assess behavior, including the Variable Delay to Signal (VDS), the Five Choice Serial Reaction Time Task (5-CSRTT), the Delay Discounting Task (DDT), and the Rodent Gambling Task (rGT). Genetic analyses were performed on the frontal cortex, and metabolomics and fatty acid profiles were examined using stool samples collected on PND298. Results: The study revealed that rats exposed to the HFD exhibited heightened impulsivity in the VDS and in the 5-CSRTT, suggesting an increase in motor impulsivity. Notably, no significant effect was observed in the DDT. Surprisingly, the HFD-exposed group demonstrated reduced levels of impulsive-like behaviors, and a different decision making, in the rGT. Furthermore, abnormal gene regultation linked to brain plasticity and dopamine were identified in the frontal cortex. Metabolomics analysis of stool samples, collected in adulthood, indicated lower levels of fatty acids. Discussion: These results suggest that HFD exposure during adolescence may create a lasting vulnerability to inhibitory control deficits, specifically in terms of motor impulsivity, and in gene expression as well as in metabolomics profile. |
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