bioRxiv Subject Collection: Neuroscience's Journal
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Sunday, June 22nd, 2025
| Time |
Event |
| 1:52p |
Non-cell autonomous control of presynaptic remodeling by the hypothalamic autophagy/NPY axis
Macroautophagy/autophagy, a critical cellular degradation pathway essential for maintaining neuronal proteostasis, declines with age and has been increasingly implicated in the regulation of synaptic integrity and circuit resilience. Neuropeptide Y (NPY), the most abundantly expressed neuropeptide in the mammalian brain, has emerged as a key modulator of both autophagy and aging-related processes. In Drosophila, the NPY-family peptide short Neuropeptide F (sNPF) has been shown to causally influence aging-associated changes in synaptic architecture and function, particularly at the presynaptic active zone (AZ), via non-cell autonomous mechanisms.
Extending this concept to mammals, we investigated whether NPY and autophagy interact within NPY-secreting neurons to regulate age-related AZ remodeling. Our results indicate that hypothalamic NPY/AgRP neurons may exert geroprotective effects through the release of NPY and potentially other signaling molecules, thereby influencing both metabolic homeostasis and brain-wide synaptic function. These data suggest a conserved role for autophagy in maintaining presynaptic organization and resilience during aging. | | 1:52p |
Hierarchical microstructural tissue growth of the gray and white matter of human visual cortex during the first year of life
Development of gray and white matter tissue microstructure is critical for the emergence of sensory and cognitive functions. However, it is unknown how microstructural tissue properties of the human visual system develop in the first year of human life. Here, we use tissue relaxation rate (R1) obtained using quantitative MRI to measure the longitudinal development of gray and white matter in brain areas spanning three visual processing streams: dorsal, lateral, and ventral, during the first year of life. R1 in gray and white matter of all visual regions in the three processing streams increases postnatally, indicating microstructural tissue growth. R1 increases faster between 0-6 months than 6-12 months, and faster in white matter than gray matter, with white matter R1 surpassing that of gray matter after two months of age. Strikingly, this microstructural growth is hierarchical: across all streams, early visual areas are more mature at birth than higher-level areas but develop more slowly postnatally than higher-level areas. The exception is TO1 (MT) which is similar to V1: it is microstructurally more mature at birth and develops slower than neighboring areas. Overall, our findings provide the first comprehensive measurement of microstructural tissue growth in infancy across three visual processing streams and propose a new hypothesis that functional development of the visual cortex may be coupled with microstructural development and follows a similar hierarchical trajectory. | | 1:52p |
Nicotinic Modulation of Fast-spiking Neurons in Rat Somatosensory Cortex Across Development
Signaling at nicotinic acetylcholine receptors (nAChRs) is vital for normal development of cerebral cortical circuits. These developing circuits are also shaped by fast-spiking (FS) inhibitory cortical neurons. While nicotinic dysfunction in FS neurons is implicated in a number of psychiatric and neurodevelopmental disorders, FS neurons are thought to not have nicotinic responses in adults. Here, we establish a timeline of FS neuron response to nicotine pre- and postsynaptically in primary somatosensory cortex in male and female rats. We found that nicotine increases the frequency of spontaneous synaptic inputs to FS neurons during the second postnatal week, and this effect persisted through development. In contrast, FS neurons in S1 had no postsynaptic responses to nicotine from as early as they can be reliably identified. This was not attributable to receptor desensitization, and we further revealed that FS neurons express abundant mRNA for several nAChR subunits, beginning early in development. To determine why FS neurons do not respond to nicotine, despite expressing these receptors, we probed for the expression of lynx1, a negative nicotinic modulator. Lynx1 mRNA was expressed in FS neurons from early development, with expression increasing dramatically during the second postnatal week.
SIGNIFICANCE STATEMENTSignaling at nicotinic receptors is critical for development of cortical circuits. These circuits are also shaped by fast-spiking (FS) inhibitory neurons. We reveal how these developmental processes interact, by establishing a timeline of nicotinic effects on FS neurons in rats. We find that nicotine presynaptically regulates inputs to FS neurons from early development. However, FS neurons at all ages lack postsynaptic responses to nicotine, despite expressing nicotinic receptor mRNA. This might be due to the expression of lynx1, a negative nicotinic receptor modulator, which we identify in FS neurons as early as the first postnatal week. This work reveals novel aspects of development, relevant to both normal cortical development and the neuropsychiatric pathologies associated with abnormal FS neurons and nicotinic development. | | 1:52p |
EEG-based Decoding of Auditory Attention to Conversations with Turn-taking Speakers
ObjectivesAuditory attention decoding (AAD) refers to the process of identifying which sound source a listener is attending to, based on neural recordings, such as electroencephalography (EEG). Most AAD studies use a competing speaker paradigm where two continuously active speech signals are simultaneously presented, in which the participant is instructed to attend to one speaker and ignore the other speaker. However, such a competing two-speaker scenario is uncommon in real life, as speakers typically take turns rather than speaking simultaneously. In this paper, we argue that decoding attention to conversations (rather than individual speakers) is a more relevant paradigm for testing AAD algorithms. In such a conversation-tracking paradigm, the AAD algorithm focusses on switching between entire conversations, resulting in less frequent attention shifts (ignoring turn-taking within conversations), thereby allowing for more relaxed constraints on the decision time.
DesignTo test AAD performance in such a conversation-tracking paradigm, we simulated a challenging restaurant scenario with three simultaneous two-speaker conversations, which were podcasts presented in front of the listener and in the back left and back right of the room. We conducted an EEG experiment on 20 normal-hearing participants to compare the performance of AAD in the commonly used competing speaker paradigm with two speakers versus the conversation tracking paradigm with 2 or 3 conversations, each containing two turn-taking speakers.
ResultsWe found that AAD, using stimulus decoding, worked well under all experimental conditions, and that the accuracy was not influenced by the direction of attention, the proximity to the target conversation, or the presence of within-trial attention switches (versus a condition with sustained attention). Given the challenging scenario, we probed for the participants listening experience and found a correlation between the neural decoding performance and the perceived listening effort and self-reported speech intelligibility. To gain insight into the speech intelligibility of the participants in our setup, they performed a speech-in-noise test (Flemish matrix sentence test), but we did not find a correlation between the speech intelligibility performance and the AAD performance. | | 2:19p |
Projection-Specific Intersectional Optogenetics for Precise Excitation and Inhibition in the Marmoset Brain
The primate cerebral cortex relies on long-range connections to integrate information between functionally specialized areas. Investigating these processes requires tools that can selectively modulate specific projection pathways. While cell-class-specific optogenetics can modulate local circuits, these approaches often lack pathway specificity. Projection-specific optogenetics offers greater precision, especially in primates, where cortical areas are spatially and functionally well-separated. To address challenges in translating this approach from rodents to primates, we developed a mouse-to-marmoset pipeline. We first validated that optogenetic targeting of inhibitory neurons (AAV9-Dlx-ChR2) effectively silenced local cortical areas in marmosets. We then tested selective excitation and inhibition of defined projection pathways. By intersecting retrogradely delivered Cre-recombinase (AAVretro-Cre) with locally injected Cre-dependent opsins (AAV8-FLEx-ChR2 or Jaws), we achieved efficient, direction-specific labeling of both callosal and longitudinal projections. This intersectional strategy enabled precise excitatory and inhibitory control of cortical activity using distinct light wavelengths, advancing projection-specific optogenetics for investigating primate brain circuit function.
Graphical Abstract
O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=71 SRC="FIGDIR/small/660378v1_ufig1.gif" ALT="Figure 1">
View larger version (20K):
org.highwire.dtl.DTLVardef@c6fd34org.highwire.dtl.DTLVardef@1997b0org.highwire.dtl.DTLVardef@35bb75org.highwire.dtl.DTLVardef@1a607aa_HPS_FORMAT_FIGEXP M_FIG A: Local suppression of cortical activity that is non-selective across cell classes can be accomplished by excitation of inhibitory interneurons expressing mDlx-ChR2 yielding broad inhibition. B: By contrast, targeting a specific cortico-cortical projection pathway for suppression can be accomplished through an intersectional approach. For a successful intersection, a retrograde AAV carrying hSyn-Cre is injected at the projection terminal and a locally expressing AAV carrying CAG-FLEx-opsin is injected at the soma. These viruses meet at the nucleus and yield opsin expression restricted to projection neurons. C: Inhibition or excitation is possible in targeted projection neurons due to co-expression of the blue light triggered excitatory opsin ChR2 or the red shifted inhibitory opsin Jaws.
C_FIG | | 2:19p |
Dynamic cholinergic signaling differentially desynchronizes cortical microcircuits dependent on modulation rate and network topology
Acetylcholine (ACh) affects both the intrinsic properties of individual neurons and the oscillatory tendencies of neuronal microcircuits by modulating the muscarinic-receptor gated m-current. However, despite contemporary experimental evidence of ACh concentrations changing at millisecond timescales, computational studies traditionally model ACh solely as a tonic neuromodulator. How time-varying, dynamic cholinergic modulation of the m-current affects the dynamics of neuronal microcircuits therefore remains an open question. Using a new implementation of a time-varying cholinergic signal in computational excitatory-inhibitory (E-I) spiking neuronal networks, we here delineate how the interaction between dynamic cholinergic modulation and network topology influences the oscillatory tendencies of these systems. While the dynamics of networks with dominant inter-connectivity (strong E-to-I and I-to-E synaptic weights) are minimally affected, networks with dominant intra-connectivity (strong E-to-E and I-to-I synaptic weights) exhibit dynamics heavily dependent upon dynamic cholinergic signaling. Further investigation of these latter type of networks reveals that their firing patterns are sensitive to the timecourse of cholinergic modulation and that relatively minor changes to the E-I connectivity strength promote distinct desynchronization mechanisms. Our results indicate that network topology plays a paramount role in dictating the modulatory effects of time-varying cholinergic signals, a finding of broad relevance to our understanding of cholinergic modulation and potentially impactful in the design of neurostimulation therapies believed to act through cholinergic pathways.
Author summaryAcetylcholine (ACh) is a chemical messenger that alters the intrinsic properties of neurons and in turn regulates brain activity related to cognitive functions such as sensory processing, memory formation, and attention. Although mounting experimental evidence shows that ACh concentrations in the brain can change dynamically at rapid timescales, computational studies conventionally consider ACh concentrations as constant across time. This motivated us to create a computational model of a neuronal microcircuit in which cellular properties are affected by ACh concentrations varying at millisecond-level timescales. The oscillatory dynamics of this microcircuit differ in important ways from similar systems with constant ACh levels, with the influence of dynamically changing ACh critically dependent upon the connectivity of the neurons in the modeled brain region. These results describe novel mechanisms by which ACh controls microcircuit activity overlooked in existing models in which ACh varies only over long timescales, an understanding which may be vital for the refinement of neurostimulation therapies believed to act through transient alterations to ACh activity. | | 2:19p |
Post Adversity Changes in Nigro-Striatal Dopamine: a Mechanism for Anxiety Induced Exacerbated Innate Repetitive Behaviors.
Anxiety exacerbates symptoms in various psychiatric disorders. In conditions such as obsessive-compulsive disorder (OCD) or Tourette syndrome, anxiety intensifies stereotypic and repetitive behaviors. Rodent self-grooming, a structured, repetitive innate behavior, serves as an effective rodent platform for studying these behaviors in neuropsychiatric research. Anxiety is also linked to altered functioning of the dopamine (DA) system, particularly within the substantia-nigra pars compacta (SNc), the main DA source to the dorsal striatum through the nigro-striatal pathway. Striatal modulation by DA signal also plays a complex role in repetitive behaviors and OCD-like symptoms, suggesting this system as linking anxiety to the induced exacerbation of repetitive behavior. In the present study, we observed several long-term effects of anxiety inducing foot shock on grooming behavior. Recordings single unit neuronal activity in the SNc revealed distinct response patterns related to grooming behavior with changes in the magnitude and timing following the shock treatment. Notably, DA neurons of different nigro-striatal pathways demonstrated different changes in different response pattern type units. DA neurons projecting to the dorsolateral striatum (DLS) showed increase, while those targeting the dorsomedial striatum (DMS) exhibited decrease in transient activity -suggesting a shift in cortico-striatal circuitry of behavioral control. These neural changes were correlated with the observed behavioral alterations following adversity. Furthermore, targeted stimulation of DLS-projecting DA neurons rescued the anxiety-induced behavioral effects, highlighting the critical role of the nigro-striatal pathway to the DLS in mediating the interaction between anxiety and repetitive behaviors, thus offering future direction for mitigation of relevant psychiatric symptoms. | | 2:19p |
Brain Region-Specific Gene Co-expression Networks Reveal Neuroinflammation and ER Stress Signatures in Major Depressive Disorder
This study aims to investigate gene expression changes in different brain regions of Major Depressive Disorder (MDD) patients using transcriptomics and bioinformatics approaches. Through differential expression gene (DEG) analysis, functional enrichment analysis, and Weighted Gene Co-expression Network Analysis (WGCNA), we aimed to identify key genes, pathways, and co-expression modules associated with MDD, with particular emphasis on the role of neuroinflammation and endoplasmic reticulum (ER) stress pathways in MDD pathology and their region-specific characteristics. The findings of this study will provide novel insights into the complex molecular mechanisms of MDD and lay the foundation for the future development of diagnostic biomarkers and therapeutic targets. |
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