Neurodegenerative diseases involve disruption of healthy brain network communication occurring before the emergence of symptoms. Magnetoencephalography (MEG) is sensitive to the magnetic fields generated by cortical neuronal activity, and the most spatio-temporally accurate method of directly assessing neuronal activity non-invasively. We used MEG to directly compare three neurodegenerative disorders against a large healthy cohort to characterise patterns of activity deviating from healthy ageing. Task-free MEG recordings were acquired from patients with Alzheimer's disease (AD, n=29), Parkinson's disease (PD, n=25), amyotrophic lateral sclerosis (ALS, n=33) and healthy controls (HC, n=191). Healthy ageing trajectories for metrics including spectral power (local neuronal recruitment), connectivity (long-range communication), 1/f exponent (which may reflect inhibition), and oscillatory speed were extracted. These metrics were compared pairwise between HC and patient groups, correcting for age and sex. The modelled trajectories of healthy ageing included increasing beta power and oscillatory speed, with reduced power spectrum slope. PD, AD, and ALS groups all showed reductions in beta power and slowing of oscillatory activity compared to matched HC. In AD, older patients showed lower beta power compared to younger patients. Compared to matched HC, the power spectrum slope was uniquely reduced in ALS, in contrast to the increase seen in PD and AD. Gamma connectivity increased in AD and ALS. MEG has unique potential as a source of biomarkers that might be used to detect deviation from healthy ageing if applied at an earlier presymptomatic stage of neurodegeneration than current tools permit. It might also provide outcome measures for prevention trials.

While the respiratory rhythm is increasingly recognized as a key modulator of oscillatory brain activity across the wake-sleep cycle in humans, very little is known about its influence on aperiodic brain activity during sleep. This broadband activity indicates spontaneous fluctuations in excitation-inhibition (E:I) balance across vigilance states and has recently been shown to systematically covary across the respiratory cycle during waking resting state. We used simultaneous EEG and respiratory recordings over a full night of sleep collected from N = 23 healthy participants to unravel the nested dynamics of respiration phase-locked excitability states across the wake-sleep cycle. We demonstrate a robust phase shift in the coupling of aperiodic brain activity to respiratory rhythms as participants were transitioning from wakefulness to sleep. Moreover, respiration-brain coupling became more consistent both across and within participants, as interindividual as well as intraindividual variability systematically lessened from wakefulness and the transition to sleep towards deeper sleep stages. Our results suggest that respiration phase-locked changes in E:I balance conceivably add to sleep stage-specific neural signatures of REM and NREM sleep, highlighting the complexity of brain-body coupling during sleep.

The superior colliculus (SC) integrates multisensory inputs from retinal, subcortical, and cortical regions within a map of visual space to support orienting and interactive behaviors. While early models suggested that the SC primarily represents peripheral space for target detection, recent evidence highlights its significant foveal representation, essential for precisely targeting objects. Using ultra-high-resolution phase-encoding fMRI and spatially localized stimuli, we mapped the visuotopic organization of the SC in six macaques up to 40° eccentricity. In addition to confirming previous findings, we identified consistent interhemispheric asymmetries in the fMRI signal. The left SC, unlike the right, displayed a clear eccentricity map with a smooth rostro-caudal progression of responses to stimuli of increasing eccentricity from the fovea to the periphery. Conversely, the right SC showed no evidence of a pronounced eccentricity map and, instead, it exhibited more prominent polar angle maps and spatially broader fMRI responses to peripheral stimuli compared to the left SC. These lateralized responses were consistent across stimulus types and imaging protocols and were mirrored only in the intraparietal sulcus, a major cortical input to the SC. The observed asymmetry may derive from differences in magnification factor, intercollicular or surround inhibition between the left and right SC. Regardless of the underlying mechanism, our results suggest that functional lateralization in nonhuman primates may be more prevalent than previously recognized.

Advanced EEG technology has revealed that epileptiform activity occurs more frequently in Alzheimer's disease (AD) than previously recognized, prompting debate over the utility of EEG in AD diagnostics. Yet, unlike epilepsy, epileptiform activity is not always observed in AD, leading to skepticism. Historically, this absence has been attributed to limited recording depth or insufficient recording duration. We tested an alternative hypothesis that certain types of epileptiform activity, specifically high frequency oscillations (HFOs, defined as 250-500 Hz fast ripples), inhibit interictal spikes (IIS), which are currently used to assess hyperexcitability clinically. We recorded wideband (0.1-500 Hz) hippocampal local field potentials in three AD (Tg2576, Presenilin 2, Ts65Dn Down syndrome model) and two epilepsy (intrahippocampal kainic acid, pilocarpine) mouse models during wakefulness and sleep. In both AD and epilepsy, HFOs consistently outnumbered IIS across behavioral states, age and recording contact. However, IIS and HFOs showed divergent relationships: a negative correlation between their rates was observed only in AD, in contrast to a positive correlation in epilepsy. HFOs preceded IIS at much shorter intervals in epilepsy than in AD. Co-occurrence of IIS with ripples did not differ between AD and epilepsy. These findings reveal a novel dissociation between clinically-relevant EEG biomarkers in AD and epilepsy. In AD, HFOs may inhibit IIS, which could lead to underestimation of hyperexcitability and hinder patient stratification for anti-seizure therapies. While non-invasive HFO detection remains challenging, we stress the need for wideband EEG/MEG, particularly in AD, to assess the full extent of hyperexcitability and biomarker interactions that would otherwise remain undetected.

Dopamine modulates brain functions such as memory and learning, and studies into underlying mechanisms have been largely focused on glutamatergic synapses and their plasticity. Much less is known about the dopaminergic modulation of inhibitory plasticity at synapses formed by distinct GABAergic interneurons targeting different cells. Herein, we addressed the role of D1-type dopamine receptors (D1Rs) in inhibitory plasticity at synapses between interneurons (INs) and pyramidal cells (PCs), as well as between INs in the CA1 region. Activation and blockade of D1Rs increased and reduced the mIPSCs amplitude (measured from PCs), respectively, while the decay kinetics was prolonged, indicating a complex postsynaptic mechanism. We also checked the D1Rs effect on heterosynaptic NMDA-induced inhibitory long-term potentiation (iLTP) measured at PCs and found that blockade of D1Rs converted iLTP into inhibitory long-term depression (iLTD), whereas D1Rs activation slightly diminished iLTP. NMDA-induced iLTP in synapses formed by parvalbumin- (PV) positive INs on PCs was reduced to zero by SKF, while SCH converted iLTP to iLTD. Interestingly, NMDA-induced iLTP in the somatostatin- (SST) positive INs was reversed to iLTD by both SKF and SCH, while these compounds were ineffective on baseline activity, and these effects were mirrored by changes in gephyrin clusters. Thus, the impact of D1Rs on inhibitory plasticity observed at the SST INs and PCs showed differences with respect to baseline activity, NMDA-induced plasticity, and the kinetics of synaptic currents. Altogether, we show that D1Rs modulate inhibitory long-term plasticity in a manner dependent on the presynaptic and target neurons.

Cocaine use disorder is a significant global health issue, and despite its widespread impact, effective treatments are lacking. While research has largely focused on the underlying neuronal mechanisms, the role of astrocytes, key regulators of synaptic transmission and plasticity, remains underexplored. Using a multidisciplinary approach that combines immunohistochemistry, electron microscopy, 3D cell reconstruction, viral gene transfer, and behavioral assays, we investigated the early adaptive responses of astrocytes to repeated cocaine administration. We report that cocaine administration induces astrocyte reactivity in the nucleus accumbens, characterized by structural remodeling, reduced synaptic coverage, and upregulation of reactivity-associated markers, including STAT3. Furthermore, we demonstrated that the JAK/STAT3 signaling pathway plays a critical role in the pathological structural astrocytic responses and in the cocaine-induced motor behavior. Our findings highlight astrocytes as pivotal players in the initial neural adaptations underlying cocaine-induced behavior. These data may provide a basis for the development of novel therapeutic strategies targeting astrocytes to address the structural and functional disruptions associated with cocaine exposure.

We investigated the effect of systemic administration of the synthetic oxytocin (OXT) analog carbetocin and/or OXT receptor antagonists (atosiban and L-368,899) on social avoidance and anxiogenic-like effect in male rats subjected to chronic social defeat stress (cSDS). Effect of cSDS and pharmacological manipulation of OXT system on expression of OXT receptor within the medial prefrontal cortex (mPFC) subregions [anterior cingulate (Cg), prelimbic (PL) and infralimbic (IL) cortices] was also evaluated. Our behavioral results indicated that cSDS, while not inducing social avoidance in the social interaction test, reliably induced anxiogenic-like effect as measured by the elevated plus maze test. Chronic systemic treatment with either carbetocin or atosiban, but not L-368,899, during cSDS protocol dose-dependently prevented the anxiogenic-like effect. Both atosiban and L-368,899 inhibited the anxiolytic effect of carbetocin in defeated animals, confirming OXT receptor-mediated effect. Also, cSDS increased OXT receptor levels within the Cg, which was inhibited by both atosiban and L-368,899 treatments. Conversely, cSDS did not affect OXT receptor within the PL and IL. However, carbetocin treatment increased OXT receptor expression within the PL and IL of defeated animals, an effect that was blocked by either atosiban or L-368,899. Taken together, our study provides evidence for the critical role of the OXT system and its pharmacological manipulation in modulating anxiogenic-like effects evoked by social stress. Furthermore, the region-specific modulation of OXT receptor expression within the mPFC by stress and OXT system pharmacological manipulation emphasize the complex and dynamic nature of OXT receptor regulation in brain regions crucial for emotional processing.

Major depressive disorder (MDD) is a widespread and disabling condition whose etiology and pathophysiology are not fully understood. Furthermore, pharmacological treatment of MDD poses challenging aspects, including delayed therapeutic effects, ineffectiveness against the so-called "residual symptoms", and a high proportion of non-responder patients. On these bases, it is crucial to recognize the key molecular systems and mechanisms involved in the pathophysiology of MDD in order to improve diagnostic tools and develop more effective pharmacological strategies. In this context, proteomics is a highly effective tool for simultaneously identifying and quantifying a large number of proteins within biological samples. This review will describe and discuss proteomic data from stress-based experimental models of MDD as well as from human brains and bodily fluids (e.g., cerebrospinal fluid and plasma), with the aim of elucidating the neurobiological counterparts of this psychiatric disorder. These findings will be summarized in an attempt to provide comprehensive maps of the biological systems involved in MDD, offering new insights into the molecular basis of different disease subtypes and paving the way to personalized diagnostic and treatment strategies.

In the last two decades, many gene mutations have been identified that when homozygous, lead to childhood neurological disorders, but when heterozygous, result in adult-onset neurodegenerative disease. A shared feature linking these genes? They encode proteins residing in or impacting the function of the lysosome, a key organelle in macromolecular degradation and recycling whose loss leads to the inability to manage proteostatic stress. Here, we propose that lysosomes connect a subset of genetic neurological and neurodegenerative disorders as they occur in two distinct life epochs-development and aging-that endure high levels of proteostatic and other physiological stresses. In this Perspective, we highlight the differing mechanisms of three genes that exemplify this link: glucocerebrosidase A (GBA: Gaucher's disease and Parkinson's disease), progranulin (GRN: neuronal ceroid lipofuscinosis and frontotemporal dementia), and tuberous sclerosis complex 1 (TSC1: tuberous sclerosis complex and frontotemporal dementia). We discuss why neurons seem particularly vulnerable to lysosomal dysfunction and ways in which lysosomes potentially contribute to selective neuronal vulnerability. Finally, as disrupted lysosomal catabolism of macromolecules connects these diseases of the nervous system, we propose that they be jointly conceptualized as "Lysosomal Clearance Disorders."

Neuronal dendrites integrate excitatory input. They can perform local computations such as coincidence detection by amplifying synchronized local input and dendritic spiking. Extracellular glycine could be a powerful modulator of such processes through its action as a co-agonist at glutamate receptors of the N-methyl-D-aspartate (NMDA) subtype but also as a ligand of inhibitory glycine receptors (GlyRs). Similarly, glycine transporters (GlyTs), an emerging drug target for psychiatric and other diseases, could control dendritic integration through ambient glycine levels. Both hypotheses were tested at dendrites of CA1 pyramidal cells in acute hippocampal slices by pharmacologically analysing how glycine, GlyTs and GlyRs change the postsynaptic response to local dendritic excitatory input. Using microiontophoretic glutamate application, we found that glycine can indeed significantly increase dendritic excitability and dendritic spiking. We also uncovered that GlyTs are powerful modulators of dendritic spiking, which can limit the impact of glycine sources on CA1 pyramidal cells. Our experiments also revealed that GlyRs can have an opposite, inhibitory effect on the slow dendritic spike component. This directly demonstrates that glycine can dynamically enhance dendritic responsiveness to local input and promote dendritic spiking, while GlyTs and GlyRs have an opposing effect. Together, this makes glycinergic signalling a powerful modulator of the nonlinear integration of synaptic input in CA1 radial oblique dendrites.

Social interactions are a hallmark of animal behavior and is essential for survival, cooperation, and reproduction. Despite its necessity, the neural mechanisms that drive social behavior, particularly the rewarding nature of social interactions, are not fully understood. Social behaviors are inherently rewarding, and this intrinsic value plays a key role in reinforcing and shaping social engagement. A growing body of work has sought to quantify social reward in rodents using behavioral paradigms such as social conditioned place preference and operant social motivation tasks, offering translational tools to probe underlying circuit mechanisms. Historically, this research has centered on the mesolimbic dopamine pathway, particularly the ventral tegmental area and its projections to the nucleus accumbens. However, emerging evidence supports a complementary role for prefrontal cortical (PFC) circuits in modulating social motivation and reward. The PFC integrates contextual and social information via distinct neuronal populations and exerts top-down control over behavior through its projections to subcortical targets such as the ventral striatum (vSTR). While prior research has implicated the PFC-vSTR pathway in general aspects of social behavior, its specific contribution to the encoding of social reward remains poorly defined. Here, we synthesize existing findings and propose a novel mechanism in which prefrontal parvalbumin (PV) interneurons regulate social reward by modulating PFC-vSTR output. We further consider how neuromodulators such as oxytocin and dopamine interact with this circuit to further influence social behavior. Elucidating the microcircuit-level control of social reward has significant implications for neuropsychiatric disorders, including autism spectrum disorder and schizophrenia, where social motivation and reward processing are often disrupted.

Layer 6b (L6b) neurons are a sparse population of deep neocortical neurons that govern both healthy and disordered brain states. L6b neurons have qualitatively been characterized as a thin lamina within the deepest layer of the cerebral cortex, yet the precise cell-type-specific properties and spatial organization of these neurons across the cortical mantle remain unresolved. Here, we combine single-cell RNA sequencing, highly multiplexed fluorescent in situ hybridization, and single-cell spatial transcriptomics to comprehensively characterize L6b cell-type identity, molecular heterogeneity, and spatial organization. In doing so, we identify and spatially resolve multiple distinct L6b subtypes with unique molecular signatures. To investigate the spatial organization of these subtypes across the brain, we generated a single-cell spatial transcriptomics dataset comprising 450,496 cells, offering the most extensive spatial mapping of L6b subtypes to date. Using a data-driven approach to analyze this dataset, we identify that the spatial patterning of L6b varies across the cortical mantle according to a patchwork-like composition of subtypes, which can notably extend beyond the classically defined deep location of L6b for some subtypes. We also find that L6b neurons can be transcriptionally separable but spatially intermingled with Layer 6a neurons, illustrating that a deep location within the cortex is neither sufficient nor necessary for assessing L6b identity. Our work provides the most comprehensive cellular phenotyping of L6b to date, reveals a cell-type-specific spatial-molecular framework for interpreting L6b properties and function, and will guide future investigations on the role of L6b cell subtypes and molecules in brain health and disorder.

Binocular rivalry (BR) is a fascinating phenomenon in which the presentation of two different images to each eye leads to alternating perceptual experiences. During BR, cortical activation is influenced by both stimulus-related factors (e.g., image incongruence) and top-down cognitive processes such as attention. Disentangling the contributions of these factors has remained a challenge. Anesthetized animal models offer a unique opportunity to isolate purely stimulus-driven neural activity, eliminating confounds from higher cognitive and behavioral processes. Using two-photon calcium imaging, we recorded neuronal responses to BR stimuli in areas V1 and V2 of anesthetized macaques. We found that under BR stimulation, V1 neurons exhibited ongoing response fluctuations whose magnitude varied across cells and closely resembled activity patterns during physical stimulus alternation (SA). Key characteristics of these fluctuations mirrored those typical of perceptual BR. The strength of fluctuation in individual neurons correlated with their ocular dominance and orientation selectivity. Similar patterns observed in V2 suggest that such rivalry-like activity propagates along the visual hierarchy. Together, these results demonstrate that early sensory mechanisms in V1 can generate BR-like alternations independently of conscious processing.

Lumbar spinal stenosis (LSS) is one of the most common spinal disorders in elderly people and is often accompanied by neuropathic pain. Although our previous studies have demonstrated that infiltrating macrophage contribute to chronic neuropathic pain in LSS rat model, the molecular mechanisms underlying macrophage activation and infiltration have not been fully elucidated. In this study, we examined the critical role of platelet-derived growth factor receptor (PDGFR) signaling pathway in neuropathic pain associated with macrophage infiltration and activation in LSS rats. The LSS rat model was induced by cauda equina compression using a silicone block placed within the epidural spaces of the L5-L6 vertebrae, with neuropathic pain developing four weeks after compression. We found that the PDGFR and Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathways were upregulated in infiltrated macrophages at 28 days in the LSS model. Administration of the PDGFR inhibitor imatinib significantly alleviated LSS-induced macrophages activation and infiltration. Imatinib also reduced LSS-induced chronic mechanical allodynia and inhibited the expression of inflammatory mediators including tumor necrosis factor alpha (TNF-α), interleukin beta (IL-1β), interleukin 6 (IL-6), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS). Furthermore, imatinib significantly alleviated the activation of RAW 264.7 macrophage cell line by lipopolysaccharide (LPS). These findings suggest that PDGFR signaling mediates neuropathic pain by promoting macrophage infiltration and activation following cauda equina compression and may serve as a potential therapeutic target for neuropathic pain in LSS patients.

Humans live in an environment that contains rich auditory stimuli, which must be processed efficiently. The entrainment of neural oscillations to acoustic inputs may support the processing of simple and complex sounds. However, the characteristics of this entrainment process have been shown to be inconsistent across species and experimental paradigms. It is imperative to establish whether neural activity in response to speech is a result of combination of simple evoked responses or of entrainment of neural oscillations in human participants. In this study, 12 participants with intracranial electrodes listened to natural speech and neural entrainment as evidenced by oscillatory activity persisting beyond the evoked responses was assessed. Neural activity was recorded from 165 contacts in Heschl's gyrus and superior temporal gyrus. First, acoustic edges in the speech envelope induced coherence between speech and auditory cortex activity. Further, entrainment in the theta-alpha band outlasted the acoustic stimulation. This activity exceeded what could be expected from a simple evoked response. These findings suggest that speech has the potential to entrain neural oscillations in the human auditory cortex.

Pair bonding (PB) is a stable affiliative relationship that confers profound behavioral and physiological advantages. The prairie vole (Microtus ochrogaster), one of the few socially monogamous mammals, provides a tractable model for dissecting the neurobiological substrates of social interactions. We previously showed that social co-habitation with mating (SCM) increases cell proliferation and neuronal differentiation in the subventricular zone (SVZ) and dentate gyrus (DG), implicating adult neurogenesis in bond formation. Here, we characterized the underlying molecular programs by bulk RNA-seq of the SVZ, DG and nucleus accumbens (NAc) at two time points, 48 h and 120 h, following SCM or isolated (control) housing. Across ∼ 18000 expressed genes, 286 differentially expressed genes (DEGs) emerged in the female SVZ and 540 in the females DG (120 h vs 48 h SCM), whereas male niches displayed markedly fewer transcriptional shifts, confirming pronounced sexual dimorphism. Gene ontology analysis revealed sustained upregulation of mitochondrial and oxidative-phosphorylation modules, coupled with downregulation of neurogenesis, synaptic plasticity, and cell migration pathways in females at 120 h. In vitro, SVZ-derived neurospheres from females mirrored these signatures: SCM increased the sphere number at 48 h, but neuronal output normalized by 120 h, indicating a transient neurogenic surge. Numerous zinc-finger transcripts and unannotated long non-coding RNAs were also regulated, hinting at vole-specific epigenetic controls. Strikingly, > 100 DEGs mapped to human psychiatric-risk loci. Autism disorder spectrum (ADS) and schizophrenia-associated orthologues (e.g., GRIN2A/B, KMT2A, UBE3A) were predominantly downregulated during bond consolidation in females, whereas isolation elevated major depressive disorder (MDD) markers (e.g., CACNA1H) in both sexes. These data suggest that pair-bond formation recruits transcriptional networks that overlap the genetic architecture of neuropsychiatric diseases, and that social isolation elicits an opposing, disorder-linked profile. Together, our results identified sex-specific, temporally phased molecular pathways that couple adult neurogenesis, energy metabolism, and psychiatric-risk gene networks to the establishment of enduring social bonds.

The dynamic balance between excitatory and inhibitory (E/I) signaling is critical for hippocampal network function and memory processing. Here, we uncover a novel role for the DNA glycosylase Endonuclease VIII-like 3 (NEIL3) in maintaining this E/I balance through its impact on parvalbumin-positive (PV⁺) GABAergic interneurons. NEIL3 deficiency leads to a selective reduction in PV⁺ interneurons and impaired perineuronal net (PNN) integrity, likely contributing to further PV⁺ neuron dysfunction. These changes result in altered hippocampal oscillatory dynamics, including increased beta and low gamma power, and reduced high gamma and ripple activity. These network alterations are accompanied by distinct effects on fear memory, as demonstrated using contextual and trace fear conditioning paradigms. NEIL3-deficient mice exhibited enhanced extinction of contextual fear memory but impaired extinction of trace fear memory. These findings suggest that the integrity of inhibitory networks plays differential roles in the spatial versus temporal aspects of fear memory extinction. Transcriptomic analysis further reveals dysregulation of genes involved in glutamatergic and GABAergic signaling. Among these, Gabra2 showed a marked downregulation, potentially driven by changes in promoter DNA methylation. This work identifies NEIL3 as an important regulator of the hippocampal inhibitory network, linking PV interneuron integrity and oscillatory coordination to distinct memory outcomes, and offers potential mechanistic insight into processes that may contribute to cognitive deficits in disorders characterized by E/I imbalance.

Understanding the precise mechanisms underlying anxiety and anxiety disorders is crucial for identifying novel interventions. In this study, we report a histaminergic circuit targeting the bed nucleus of the stria terminalis (BNST) that mediates anxiety-like behavior in mice. First, we observed a significant decrease in both histamine signaling and histaminergic fiber activity in the BNST when mice entered an anxious environment. Selective modulation of the BNST-projecting histaminergic circuit mediated state-dependent anxiety behaviors: activation directly induced an anxiogenic effect on naive mice, while inhibition produced a significant anxiolytic effect in mice in an anxious state rather than normal state. Pharmacological intervention revealed that the inhibition of histamine H3 receptors (H3Rs), rather than histamine H1 receptors (H1Rs) or histamine H2 receptors (H2Rs), in the BNST abolished the anxiogenic effect of histaminergic circuit activation. Finally, through optogenetic manipulation of spatial-specific H3Rs, we identified a critical role for anxiety regulation by post-synaptic H3Rs in the BNST GABAergic neurons, rather than pre-synaptic H3Rs from upstream inputs. Together, our results revealed a histaminergic circuit targeting the BNST that mediates state-dependent anxiety-like behaviors through post-synaptic H3Rs. These findings provide new insights into the mechanism of anxiety and offer promising avenues for discovering novel pharmacological targets for the treatment of anxiety disorders.

Natural vision is an active sensing process that entails frequent eye movements to sample the environment. Nonetheless vision is often studied using passive viewing with eye position held constant. Using closed-loop eye-tracking, with saccade-contingent stimulation and simultaneous intracranial recordings in surgical epilepsy patients, we tested the critical role of eye movement signals during natural visual processing in the hippocampus and hippocampal-amygdala circuit. Prior work shows that saccades elicit phase reset of ongoing neural excitability fluctuations across a broad array of cortical and subcortical areas. Here we show that saccade-related phase reset systematically modulates neuronal ensemble responses to visual input, enables phase-coding of information across the saccade-fixation cycle and modulates network connectivity between hippocampus and amygdala. The saccade-fixation cycle thus emerges as a fundamental sampling unit, organizing a range of neural operations including input representation, network connectivity and information coding. SUMMARY: Saccade-fixation cycle: a fundamental sampling unit, organizing input representation, information coding and network coordination.

The ability to rapidly detect and respond to unexpected auditory stimuli is critical for adaptive behavior, especially during locomotion. Since movement suppresses auditory cortical activity, it remains unclear how salient auditory information influences locomotor circuits. In this work, using in vivo calcium imaging, electrophysiology, chemo- and optogenetics, we investigate the path that relays loud broadband sounds to the dorsal hippocampus (dHPC) and modulates theta oscillations. We demonstrate that noise accelerates theta frequency and decreases its power, effects mediated by entorhinal cortex (EC) and medial septum (MS) inputs while independent of the primary auditory cortex. Activation of dorsal cochlear nucleus (DCN) neurons projecting to the pontine reticular nucleus (PRN) mimics noise-driven hippocampal responses, supporting a brainstem-limbic auditory processing route. Furthermore, noise selectively modulates CA1 pyramidal neuron and interneuron activity, reflecting diverse circuit dynamics. Finally, loud broadband noise stimulus increased theta coherence between the dHPC and the medial prefrontal cortex (mPFC), enhancing interregional synchronization. These results highlight the mechanisms in which the DCN filters behaviorally relevant sounds promoting acoustic motor integration in the hippocampus during locomotion, without direct influence of the auditory cortex.

Alzheimer's disease (AD) was first described over a century ago. However, the mechanisms underlying the disease are not well understood to this day. This has negatively impacted our ability to create animal models to design and test targeted reliable treatments for the disease. Amyloid β plaque accumulation, aggregation of neurofibrillary tangles, neuroinflammation, neurodegeneration, and, of course, cognitive decline, are few of the many observed pathological features associated with AD. However, there is a concern that the animal models of AD that are based on these frameworks may not be accurately representing AD in people. As such, the results from preclinical trials have not historically translated well to the clinic. In this article, we review the current major hypotheses to describe AD; we outline the major strengths and weaknesses of the commonly used rodent models used to replicate features of these hypotheses; and we provide a strategy for the field for future research.