bioRxiv Subject Collection: Neuroscience's Journal

State dependent motor cortex stimulation reveals distinct mechanisms for corticospinal excitability and cortical responses
Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation method which can modulate brain activity by inducing electric fields in the brain. It is a popular tool to study causal brain-behavior relationships. However, brain states vary over time and affect the response of TMS. Neural oscillations can track the current brain state and are a promising marker to guide stimulation timing. Real-time, state-dependent brain stimulation has shown that neural oscillation phase modulates corticospinal excitability reflecting the connection from the primary motor cortex to a target muscle. However, such motor-evoked potentials (MEPs) only indirectly reflect motor cortex activation and are unavailable at other brain regions of interest. The direct and secondary cortical effects of phase-dependent brain stimulation remain an open question. In this study, we recorded the cortical responses during single-pulse transcranial magnetic stimulation (TMS) using electroencephalography (EEG) concurrently with the MEP measurements. TMS was delivered at peak, rising, trough, and falling phases of mu (8-13 Hz) and beta (14-30 Hz) oscillations in the motor cortex. The cortical responses were quantified through TMS-evoked potential components N15, P50, and N100 as peak-to-peak amplitudes (P50-N15 and P50-N100). We further analyzed whether the pre-stimulus frequency band power was predictive of the motor cortical responses. We found a significant main effect of neural oscillation phase on early evoked component (P50-N15). Furthermore, we found an interaction effect of oscillation phase and frequency on both early and late (P50-N100) components. Next, we compared the direct EEG response to the corticospinal excitability reflected by MEP amplitude. Interestingly, the preferred phase of the mu rhythm showed a 900 phase shift between the early TEP components and MEPs. The late component showed the same phase preference between EEG and MEPs. However, such a well-defined relationship did not exist for either of the components during beta phase specific stimulation. In addition, pre-TMS mu oscillatory power and phase significantly predicted both early and late cortical EEG responses when mu rhythm was targeted, indicating the independent causal effects of phase and power. However, only pre-TMS beta power significantly predicted the early and late TEP components when beta rhythm was targeted. Further analysis indicated that both pre-TMS mu and beta power jointly affect early cortical responses. In contrast, the late cortical responses were only influenced by pre-TMS mu power. These findings provide insight to mechanistic understanding of neural oscillation states in cortical and corticospinal activation in humans.

A third kind of episodic memory: Context familiarity is a distinct process from item familiarity and recollection
Episodic memory is accounted for with two processes: familiarity when generally recognizing an item and recollection when retrieving the full contextual details bound with the item. Paradoxically, people sometimes report contextual information as familiar but without recollecting details, which is not easily accounted for by existing theories. We tested a combination of item recognition confidence and source memory, focusing upon item-only hits with source unknown ( item familiarity), low-confidence hits with correct source memory ( context familiarity), and high-confidence hits with correct source memory ( recollection). Results across multiple within-subjects (trial-wise) and between subjects (individual variability) levels indicated these were behaviorally and physiologically distinct. Behaviorally, a crossover interaction was evident in response times, with context familiarity being slower than each condition during item recognition, but faster during source memory. Electrophysiologically, a Condition x Time x Location triple dissociation was evident in event-related potentials (ERPs), which was then independently replicated. Context familiarity exhibited an independent negative central effect from 800-1200 ms, differentiated from positive ERPs for item-familiarity (400 to 600 ms) and recollection (600 to 900 ms). These three conditions thus reflect mutually exclusive, fundamentally different processes of episodic memory. Context familiarity is a third distinct process of episodic memory.

Significance statement/SummaryMemory for past events is widely believed to operate through two different processes: one called recollection when retrieving confident, specific details of a memory, and another called familiarity when only having an unsure but conscious awareness that an item was experienced before. When people successfully retrieve details such as the source or context of a prior event, it has been assumed to reflect recollection. We demonstrate that familiarity of context is functionally distinct from familiarity of items and recollection and offer a new trivariate model. The three memory response types were differentiated across multiple behavioral and physiological measures, and at the trial level and among individual variability between-subjects, too. That is, what has traditionally been thought to be two kinds of memory processes are actually three, which become evident when using sensitive enough multi-measures. Akin to missing obvious elements when using only a two-dimensional lens to see a three-dimensional picture, when we have the ability to look for the three processes of memory, we can see them clearly dissociate and as independently replicable across several different studies of diverse cohorts from different laboratories. Together, these data reveal that context familiarity is a third process of human episodic memory.

Cognitive hyperplasticity drives insomnia
Sleep is vital for maintenance of cognitive functions and lifespan across the animal kingdom. Here, we report our surprising findings that insomniac (inc) Drosophila short sleep mutants, which lack a crucial adaptor protein for the autism-associated Cullin-3 ubiquitin ligase, exhibited excessive olfactory memory. Through a genetic modifier screen, we find that a mild attenuation of Protein Kinase A (PKA) signaling specifically rescued the sleep and longevity phenotypes of inc mutants. Surprisingly, this mild PKA signaling reduction further boosted the excessive memory in inc mutants, coupled with further exaggerated mushroom body overgrowth phenotypes. We propose that an intrinsic hyperplasticity scenario genuine to inc mutants enhances cognitive functions. Elevating PKA signaling seems to serve as a checkpoint which allows to constrain the excessive memory and mushroom body overgrowth in these animals, albeit at the sacrifice of sleep and longevity. Our data offer a mechanistic explanation for the sleep deficits of inc mutants, which challenges traditional views on the relation between sleep and memory, and suggest that behavioral hyperplasticity, e.g., prominent in autistic patients, can provoke sleep deficits.

Differences in drug intake levels (high versus low takers) do not necessarily imply distinct drug user types: insights from a new cluster-based model
Background: Classifying psychostimulant users as high and low responders based on median split of drug intake levels has face-validity: these appear to be different types of drug users. However, because psychostimulant intake levels a) are defined by an inverted U-shaped dose response (IUDR) curve, and b) do not necessarily imply motivation for the drug, it is unclear that median split-designated high and low drug responders represent different drug user types. Aims: To determine if median split-designated groups of high and low drug takers represent distinct groups when subjected to a new cluster-based model. Methods: Male Sprague Dawley rats (n = 11) self-administered cocaine doses (0.00, 0.01, 0.03, 0.1, 0.3, 0.56 and 1.00 mg/kg/infusion) to reveal the IUDR curve per individual. We derived six variables defining the structure of the IUDR curve (amplitude, mean, width, and area under the curve: AUC) and the IUDR-derived economic demand curve (consumption at zero price or Q0 and the motivation for drug or ). We compared median split and clustering of all variables (cocaine dose, IUDR/demand curves) obtained. Results: Median split of individual cocaine doses and IUDR curve-derived variables identified high versus low responders, but these groups were inconsistent with regards to group composition. Clustering of all cocaine doses revealed one cluster. Clustering of IUDR curve-derived variables revealed one cluster. Global clustering of all cocaine doses and all IUDR curve-derived variables revealed only one cluster. Conclusions: High and low drug takers do not necessarily represent distinct drug user types.

Multimodal MEG and microstructure-MRI investigations of the human hippocampal scene network
Although several studies, including our own (Hodgetts et al., 2015), have demonstrated that perceptual discrimination of complex scenes relies on an extended hippocampal network, distinct from the anterotemporal network supporting the perceptual discrimination of faces, we currently have limited insight into the specific functional and structural properties of these networks. Here, combining electrophysiological (magnetoencephalography, MEG) and microstructural (multi-shell diffusion MRI, dMRI) imaging in healthy human adults, we show that both hippocampal theta power modulation and fibre restriction of the fornix (a major input/output pathway of the hippocampus) independently related to accuracy during scene, but not face, perceptual discrimination. Conversely, inferior longitudinal fasciculus (a long-range occipito-anterotemporal tract) tissue properties correlated with face, but not scene, oddity discrimination accuracy. Our results provide new mechanistic insight into the neurocognitive systems underpinning complex scene and face perception, providing support for multiple-system representation-based accounts of the medial temporal lobe.

Sst- and Vip-Cre mouse lines without age-related hearing loss
GABAergic interneurons, including somatostatin (SST) and vasoactive intestinal peptide (VIP) positive cells, play a crucial role in cortical circuit processing. Cre recombinase-mediated manipulation of these interneurons is facilitated by commercially available knock-in mouse strains such as Sst-IRES-Cre (Sst-Cre) and Vip-IRES-Cre (Vip-Cre). However, these strains are troublesome for hearing research because they are only available on the C57BL/6 genetic background, which suffer from early onset age-related hearing loss (AHL) due to a mutation of the Cdh23 gene. To overcome this limitation, we backcrossed Sst-Cre and Vip-Cre mice to CBA mice to create normal-hearing offspring with the desired Cre transgenes. We confirmed that in these "CBA Cre" lines, Cre drives appropriate expression of Cre-dependent genes, by crossing CBA Cre mice to Ai14 reporter mice. To assess the hearing capabilities of the CBA Cre mice, we measured auditory brainstem responses (ABRs) using clicks and tones. CBA Cre mice showed significantly lower ABR thresholds compared to C57 control mice at 3, 6, 9, and 12 months. In conclusion, our study successfully generated Sst-Cre and Vip-Cre mouse lines on the CBA background that will be valuable tools for investigating the roles of SST and VIP positive interneurons without the confounding effects of age-related hearing loss.

Transcriptome-wide alternative mRNA splicing analysis reveals post-transcriptional regulation of neuronal differentiation.
Alternative splicing (AS) plays important roles in neuronal development, function, and diseases. Efforts to analyze AS transcriptome-wide in neurons remain limited. We characterized the transcriptome-wide AS changes in SH-SY5Y neuronal differentiation model, which is widely used to study neuronal function and disorders. Our analysis revealed global changes in five AS programs that drive neuronal differentiation. Motif analysis revealed the contribution of RNA binding proteins (RBPs) to the regulation of AS during neuronal development. We focused on the predominant AS program during differentiation, exon skipping (SE) events. Motif analysis revealed motifs for PTB and HuR/ELAVL1 to be the top enriched in SE events, and their protein levels were downregulated after differentiation. shRNA Knockdown of either PTB and HuR were associated with enhanced neuronal differentiation and transcriptome-wide exon skipping events driving the process of differentiation. At the level of gene expression, we observed only modest changes, indicating predominant post-transcriptional effects of PTB and HuR. We also observed that both RBPs altered cellular responses to oxidative stress, in line with the differentiated phenotype observed after KD. Our work characterizes the AS changes in a widely used and important model of neuronal development and neuroscience research and reveals intricate post-transcriptional regulation of neuronal differentiation.

Inter-individual variability in motor learning due to differences in effective learning rates between generalist and specialist memory stores
Humans exhibit large interindividual differences in motor learning ability. However, most previous studies have examined properties common across populations, with less emphasis on interindividual differences. We hypothesized here, based on our previous experimental and computational motor adaptation studies, that individual differences in effective learning rates between a generalist memory module that assumes environmental continuity and specialist modules that are responsive to trial-by-trial environmental changes could explain both large population-wise and individual-wise differences in dual tasks adaptation under block and random schedules. Participants adapted to two opposing force fields, either sequentially with alternating training blocks or simultaneously with random sequences. As previously reported, in the block training schedule, all participants adapted to the force field presented in a block but showed large interference in the subsequent opposing force field blocks, such that adapting to the two force fields was impossible. In contrast, in the random training schedule, participants could adapt to the two conflicting tasks simultaneously as a group; however, large interindividual variability was observed. A modified MOSAIC computational model of motor learning equipped with one generalist module and two specialist modules explained the observed behavior and variability for wide parameter ranges: when the predictions errors were large and consistent as in block schedules, the generalist module was selected to adapt quickly. In contrast, the specialist modules were selected when they more accurately predicted the changing environment than the generalist, as during random schedules; this resulted in consolidated memory specialized to each environment, but only when the ratio of learning rates of the generalist to specialists was relatively small. This dynamic selection process plays a crucial role in explaining the individual differences observed in motor learning abilities.

Pathogenic LRRK2 causes age-dependent and region-specific deficits in ciliation, innervation and viability of cholinergic neurons
Pathogenic activating point mutations in the LRRK2 kinase cause autosomal-dominant familial Parkinson's disease (PD). In cultured cells, mutant LRRK2 causes a deficit in de novo cilia formation and also impairs ciliary stability. In brain, previous studies have shown that in PD patients due to the G2019S-LRRK2 mutation as well as in middle-aged G2019S-LRRK2 knockin mice, striatal cholinergic interneurons show a deficit in primary cilia. Here, we show that cilia loss in G2019S-LRRK2 knockin mice is not limited to cholinergic striatal interneurons but common to cholinergic neurons across distinct brain nuclei. The lack of cilia in cholinergic forebrain neurons is accompanied by the accumulation of LRRK2-phosphorylated Rab12 GTPase and correlates with the presence of dystrophic cholinergic axons. Those deficits are already evident in young adult mutant LRRK2 mice. In contrast, the age-dependent loss of cilia in brainstem cholinergic neurons correlates with an age-dependent loss of cholinergic innervation derived from this brain area. Strikingly, we find cholinergic cell loss in mutant LRRK2 mice that is age-dependent, cell type-specific and disease-relevant. The age-dependent loss of a subset of cholinergic neurons mimics that observed in sporadic PD patients, highlighting the possibility that these particular neurons may require functional cilia for long-term cell survival.

A ternary Neurexin-T178-PTPR complex represents a core-module of neuronal synapse organization
Complexes of synaptic adhesion molecules instruct the formation, functional specification and plasticity of neuronal synapses. Proteomic and candidate gene studies have identified an array of synaptic adhesion molecules that may cooperate or provide independent columns connecting synaptic compartments, thereby, promoting the nucleation of presynaptic active zones and recruitment of postsynaptic neurotransmitter receptors. Here, we used a systematic large-scale multi-epitope affinity-purification approach (total of >120 purifications with 30 target proteins), combined with quantitative mass spectrometry to comprehensively map trans-synaptic protein networks in the mouse brain. We discover a universal presynaptic core-module consisting of the neurexin proteins and LAR-type receptor protein tyrosine phosphatases (PTPRD,S,F), linked by the tetraspanin proteins T178A, B. These ternary Neurexin-T178-PTPR complexes form through their trans-membrane domains and assemble during biogenesis in the ER. Loss of T178B results in module dissociation and loss of LAR-PTPRs. At synapses, the Neurexin-T178-PTPR module recruits stable trans-synaptic protein networks with specific pre- and post-synaptic partners and secreted extracellular linkers. These networks encompass stable associations with unique postsynaptic GABAergic and glutamatergic neurotransmitter receptor complexes, identifying the Neurexin-T178-PTPR module as a central, universal integrator of trans-synaptic signaling in the central nervous system.

Characterizing the Spatial Distribution of Dendritic RNA at Single Molecule Resolution
Neurons possess highly polarized morphology that require intricate molecular organization, partly facilitated by RNA localization. By localizing specific mRNA, neurons can modulate synaptic features through local translation and subsequent modification of protein concentrations in response to stimuli. The resulting activity-dependent modifications are essential for synaptic plasticity, and consequently, fundamental for learning and memory. Consequently, high-resolution characterization of the spatial distribution of dendritic transcripts and the spatial relationship across transcripts is critical for understanding the pathways and mechanisms underlying synaptic plasticity. In this study, we characterize the spatial distribution of six previously uncharacterized genes (Adap2, Colec12, Dtx3L, Kif5c, Nsmf, Pde2a) within the dendrites at a sub-micrometer scale, using single-molecule fluorescence in situ hybridization (smFISH). We found that spatial distributions of dendritically localized mRNA depended on both dendrite morphology and gene identity that cannot be recreated by diffusion alone, suggesting involvement of active mechanisms. Furthermore, our analysis reveals that dendritically localized mRNAs are likely co-transported and organized into clusters at larger spatial scales, indicating a more complex organization of mRNA within dendrites.

Temporal dynamics analysis reveals that concurrent working memory load eliminates the Stroop effect through disrupting stimulus-response mapping
Concurrent verbal working memory task can eliminate the color-word Stroop effect. Previous research, based on specific and limited resources, suggested that the disappearance of the conflict effect was due to the memory information preempting the resources for distractors. However, it remains unclear which particular stage of Stroop conflict processing is influenced by working memory loads. In this study, electroencephalography (EEG) recordings with event-related potential (ERP) analyses, time-frequency analyses, multivariate pattern analyses (MVPA), and representational similarity analyses (RSA) were applied to provide an in-depth investigation of the aforementioned issue. Subjects were required to complete the single task (the classical manual color-word Stroop task) and the dual task (the Sternberg working memory task combined with the Stroop task), respectively. Behaviorally, the results indicated that the Stroop effect was eliminated in the dual-task condition. The EEG results showed that the concurrent working memory task did not modulate the P1 and alpha bands. However, it modulated the sustained potential (SP), late theta (740-820 ms), and beta (920-1040 ms) power, showing no difference between congruent and incongruent trials in the dual-task condition but a significant difference in the single-task condition. Importantly, the RSA results revealed that the neural activation pattern of the late theta was similar to the response interaction pattern. Together, these findings implied that concurrent working memory task eliminated the Stroop effect through disrupting stimulus-response mapping.

Happiness promotes global processing in haptic perception
Happy and sad mood promote global and local visual processing, respectively. However, it is unclear whether mood also affects the processing level in haptic perception. Here, we used classical music to induce happy and sad mood in blindfolded participants before they scanned 3D-printed configurations with their fingers. Global shapes were triangles, circles, or squares (33mm) composed of smaller local relief shapes (3 mm): either triangles, circles, or squares. Participants explored a probe stimulus with identical local and global shapes, and two comparison stimuli, matching the probe in local, or global shape. They reported which comparison stimulus appeared more similar to the probe. In the 'sad' group, participants chose the locally-matching comparison more frequently than in the 'happy' group, revealing that sad mood promotes local processing also in touch. Overall, participants chose the globally-matching comparison more often, suggesting that global processing is more prominent in touch than assumed.

Altered Cortical Network Dynamics during Observing and Preparing Action in Patients with Corticobasal Syndrome
Besides parkinsonism, higher order cortical dysfunctions such as apraxia are hallmarks of the corticobasal syndrome (CBS). To date, little is known about the electrophysiological underpinnings of these symptoms. To shed more light on the pathophysiology of CBS, we recorded the magnetoencephalogram of 17 CBS patients and 20 age-matched controls engaged in an observe-to-imitate task. The task involved the display of a tool-use video in first person view (action observation), a written instruction to withhold movement until the presentation of a Go cue (movement preparation), and unilateral tool-use imitation. We investigated modulations of spectral power on the source level. Action observation was associated with an event-related desynchronization in the beta-band (13-30Hz), which was weaker in CBS patients than in healthy controls. The group effect localized to superior parietal, primary motor, premotor and inferior frontal cortex bilaterally. While participants awaited the Go cue, beta power was again suppressed in the hemisphere contralateral to movement, and the rate of suppression correlated with reaction time. This modulation, too, was weaker in the CBS group. Immediately before movement onset, however, beta power was similar in both groups. Our results reveal that action observation triggers beta suppression, likely reflecting motor cortical disinhibition, which is reduced in CBS patients. This pathological alteration might be a neural correlate of a selective deficit in the embedding of observed action into a motor representation (visuo-motor mapping). The suboptimal timing of the beta-power suppression to the upcoming Go cue presumably reflects a deficit in learning the trial's temporal structure rather than a deficit in movement initialization.

Auditory-motor entrainment and listening experience shape the perceptual learning of concurrent speech
Background: Plasticity from auditory experience shapes the brain's encoding and perception of sound. Though prior research demonstrates that neural entrainment (i.e., brain-to-acoustic synchronization) aids speech perception, how long- and short-term plasticity influence entrainment to concurrent speech has not been investigated. Here, we explored neural entrainment mechanisms and the interplay between short- and long-term neuroplasticity for rapid auditory perceptual learning of concurrent speech sounds in young, normal-hearing musicians and nonmusicians. Method: Participants learned to identify double-vowel mixtures during ~45 min training sessions with concurrent high-density EEG recordings. We examined the degree to which brain responses entrained to the speech-stimulus train (~9 Hz) to investigate whether entrainment to speech prior to behavioral decision predicted task performance. Source and directed functional connectivity analyses of the EEG probed whether behavior was driven by group differences auditory-motor coupling. Results: Both musicians and nonmusicians showed rapid perceptual learning in accuracy with training. Interestingly, listeners' neural entrainment strength prior to target speech mixtures predicted behavioral identification performance; stronger neural synchronization was observed preceding incorrect compared to correct trial responses. We also found stark hemispheric biases in auditory-motor coupling during speech entrainment, with greater auditory-motor connectivity in the right compared to left hemisphere for musicians (R>L) but not in nonmusicians (R=L). Conclusions: Our findings confirm stronger neuroacoustic synchronization and auditory-motor coupling during speech processing in musicians. Stronger neural entrainment to rapid stimulus trains preceding incorrect behavioral responses supports the notion that alpha-band (~10 Hz) arousal/suppression in brain activity is an important modulator of trial-by-trial success in perceptual processing.

Brain Structural Correlates of an Impending Initial Major Depressive Episode
Background: Neuroimaging research has yet to elucidate, whether reported gray matter volume (GMV) alterations in major depressive disorder (MDD) exist already before the onset of the first episode. Recruitment of presently healthy individuals with a known future transition to MDD (converters) is extremely challenging but crucial to gain insights into neurobiological vulnerability. Hence, we compared converters to patients with MDD and sustained healthy controls (HC) to distinguish pre-existing neurobiological markers from those emerging later in the course of depression. Methods: Combining two clinical cohorts (n=1709), voxel-wise GMV of n=45 converters, n=748 patients with MDD, and n=916 HC were analyzed in regions-of-interest approaches. By contrasting the subgroups and considering both remission state and reported recurrence at a 2-year clinical follow-up, we stepwise disentangled effects of 1) vulnerability, 2) the acute depressive state, and 3) an initial vs. a recurrent episode. Results: Analyses revealed higher amygdala GMV in converters relative to HC (pTFCE-FWE=.037, d=0.447) and patients (pTFCE-FWE=.005, d=0.508), remaining significant when compared to remitted patients with imminent recurrence. Lower GMV in the dorsolateral prefrontal cortex (pTFCE-FWE<.001, d=0.188) and insula (pTFCE-FWE=.010, d=0.186) emerged in patients relative to HC but not to converters, driven by patients with acute MDD. Conclusion: By examining one of the largest available converter samples in psychiatric neuroimaging, this study allowed a first determination of neural markers for an impending initial depressive episode. Our findings suggest a temporary vulnerability, which in combination with other common risk factors might facilitate prediction and in turn improve prevention of depression.

Genetic Foundations of Neurophysiological and Behavioural Variability Across the Lifespan
Neurophysiological brain activity underpins cognitive functions and behavioural traits. Here, we sought to establish to what extent individual neurophysiological traits spontaneously expressed in ongoing brain activity are primarily driven by genetic variation. We also investigated whether changes in such neurophysiological features observed across the lifespan are supported by longitudinal changes in cortical gene expression. We studied the heritability of neurophysiological traits from task-free brain activity of monozygotic and dizygotic twins as well as non-related individuals recorded with magnetoencephalography. We found that these traits were more similar between monozygotic twins compared to dizygotic twins, and that these heritable core dynamical properties of brain activity are predominantly influenced by genes involved in neurotransmission processes. These genes are expressed in the cortex along a topographical gradient aligned with the distribution of major cognitive functions and psychological processes. Our data also show that the impact of these genetic determinants on cognitive and psychological traits increases with age. These findings collectively highlight the persistent genetic influence across the lifespan on neurophysiological brain activity that supports individual cognitive and behavioural traits.

Differential representation of active and passive touch in mouse somatosensory thalamus
Active and passive sensing strategies are integral to an animal's behavioral repertoire. Nevertheless, there is a lack of information regarding the neuronal circuitry that underpins these strategies, particularly at the thalamus level. We evaluated how active versus passive whisker deflections are represented in single neurons of the ventral posterior thalamus (VPM) and the posterior medial thalamus (POm) in awake mice. These are the first- and higher-order thalamic nuclei of the whisker system, respectively. VPM neurons robustly responded to both active and passive whisker deflections, while POm neurons showed a preference for passive deflections and responded poorly to active touches. This response disparity could not be explained by the animal's voluntary whisking state or stimulus kinetics. In contrast, cortical activity significantly influenced POm's responses to passive touch. Inhibition of the barrel cortex strongly attenuated whisker responses in POm and simultaneously increased the whisking phase coding. This suggests that POm receives touch information from the cortex and phase information from the brainstem. Together, these findings suggest two thalamic relay streams, where VPM robustly relays both active and passive deflection, while POm's sensitivity requires top-down cortical involvement to signal salient events such as unexpected passive deflections.

Thyroid hormones maintain parvalbumin neuron functions in mouse neocortex
Parvalbumin-expressing (PV) GABAergic interneurons play a key role in maintaining the excitation inhibition balance in the mammalian neocortex. Here we address the function of thyroid hormones in PV neurons in the mouse neocortex. To this end, Cre/loxP recombination system was used to express a dominant negative mutated receptor of thyroid hormones only in PV neurons. We analyzed the neocortical phenotype of these mice, in which thyroid hormone signaling is eliminated specifically in PV neurons, by combining genomics, histology, electrophysiology, and behavioral analysis. We found significantly altered gene expression, reduced expression of key perineuronal net components, reduced PV neuron excitability, behavioral hyperactivity and increased susceptibility to seizures. These results highlight that thyroid hormones are not only required for the differentiation of PV interneurons, but also for the maintenance of their inhibitory function after the onset of parvalbumin expression.

Neural dynamics underlying minute-timescale persistent behavior in the human brain
The ability to pursue long-term goals relies on a representations of task context that can both be maintained over long periods of time and switched flexibly when goals change. Little is known about the neural substrate for such minute-scale maintenance of task sets. Utilizing recordings in neurosurgical patients, we examined how groups of neurons in the human medial frontal cortex and hippocampus represent task contexts. When cued explicitly, task context was encoded in both brain areas and changed rapidly at task boundaries. Hippocampus exhibited a temporally dynamic code with fast decorrelation over time, preventing cross-temporal generalization. Medial frontal cortex exhibited a static code that decorrelated slowly, allowing generalization across minutes of time. When task context needed to be inferred as a latent variable, hippocampus encoded task context with a static code. These findings reveal two possible regimes for encoding minute-scale task-context representations that were engaged differently based on task demands.

Altered resting-state brain entropy (BEN) by rTMS across the human cortex
Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation method effective in treating various neuropsychiatric disorders, yet its mechanisms are not fully understood. In general, rTMS protocols are categorized into excitatory protocols including high-frequency rTMS (HF-rTMS) and intermittent theta burst stimulation (iTBS), and inhibitory protocols including low-frequency rTMS (LF-rTMS) and continuous theta burst stimulation (cTBS). Brain entropy (BEN) measures irregularity, disorders, and complexity of brain activity, our previous studies have indicated that BEN affects excitatory rTMS, including HF-rTMS and iTBS. However, two important questions remain whether rTMS is equally sensitive to inhibitory rTMS and whether it can induce opposite brain activities, another question concerns whether rTMS can induce specific changes across brain regions. To address these issues, we utilized our own cTBS targeted on the left dorsal lateral prefrontal cortex (L-DLPFC) dataset and publicly available LF-rTMS dataset with stimulating sites including the L-DLPFC, left temporal parietal junction (L-TPJ), and left occipital cortex (L-OCC), from the OpenNeuro. BEN maps were calculated before and after stimulation. The results showed that L-DLPFC cTBS increased BEN in the MOFC and L-DLPFC LF-rTMS increased BEN in the MOFC, subgenual anterior cingulate cortex (MOFC/sgACC) and putamen, the regions are consistent with our previous findings with HF-rTMS and iTBS. Additionally, L-TPJ LF-rTMS resulted in increased BEN in the right TPJ, while L-OCC LF-rTMS led to decreased BEN in the posterior cingulate cortex (PCC). Our findings suggest that BEN is not only sensitive to excitatory rTMS but also to inhibitory rTMS. Moreover, LF-rTMS induces different effects across brain regions, as detected by BEN.

A cafeteria diet blunts effects of exercise on adult hippocampal neurogenesis but not neurogenesis-dependent behaviours in adult male rats
Animal studies have shown that a cafeteria (CAF) diet (high in saturated fat and sugar), is associated with memory impairments and increased anxiety, while exercise can enhance antidepressant-like effects and cognitive function. The mechanisms underlying the effects of a CAF diet, exercise, or their convergence on memory, mood and anxiety are not fully understood, but alterations in adult hippocampal neurogenesis (AHN), gut microbial metabolites, or plasma metabolic hormones may play a role. Therefore, this study investigated whether a 7.5-week voluntary running exercise intervention in young adult male rats could alter the effects of a concurrent CAF diet on depression-like, anxiety-like and cognitive behaviours and AHN, and determined associated changes in metabolic hormones and gut microbial metabolites. We found that exercise produced a mild anxiolytic effect, regardless of diet, and increased PYY, a hormone previously shown to reduce anxiety-like behaviour. CAF diet induced differential abundance of caecal metabolites, and exercise attenuated CAF diet-induced decreases in certain metabolites implicated in cognitive function or depression-like behaviour. Although exercise exerted antidepressant-like effects in the FST, induced subtle improvements in spatial learning strategy, and increased plasma metabolic hormones previously implicated in depression-like behaviour in CAF diet-fed animals, CAF diet blunted exercise-induced increases in plasma GLP-1 and AHN, suggesting that exercise should be accompanied by a healthy diet to increase AHN. Together, these findings highlight the importance of exercise and healthy diet for hippocampal health and provide insight into potential metabolite and hormone-mediated mechanisms underlying the effects of CAF diet and exercise on brain and behaviour.