Although the neural basis of working memory (WM) capacity is often studied by exploiting interindividual differences, capacity may also differ across memory materials within a given individual. Here, we exploit the content dependence of WM capacity as a novel approach to investigate the oscillatory correlates of WM capacity, focusing on posterior 9–12 Hz alpha activity during retention. We recorded scalp electroencephalography (EEG) while male and female human participants performed WM tasks with varying memory loads (two vs. four items) and materials (English letters vs. regular shapes vs. abstract shapes). First, behavioral data confirmed that memory capacity was fundamentally content dependent; capacity for abstract shapes plateaued at around two, whereas the participants could remember more letters and regular shapes. Critically, content-specific capacity was paralleled in the degree of attenuation of EEG-alpha activity that plateaued in a similar content-specific manner. Although we observed greater a...

Temporal nesting of cortical slow oscillations, thalamic spindles, and hippocampal ripples indicates multiregional neuronal interactions required for memory consolidation. However, how the thalamic activity during spindles organizes hippocampal dynamics remains largely undetermined. We analyzed simultaneous recordings of anterodorsal thalamus and CA1 in male mice to determine the contribution of thalamic spindles in cross-regional synchronization. Our results indicated that temporal hippocampo-thalamocortical coupling was more enhanced during slower and longer thalamic spindles. Additionally, spindles occurring closer to slow oscillation trough were more strongly coupled to ripples. We found that the temporal association between CA1 spiking/ripples and thalamic spindles was stronger following spatial exploration compared with baseline sleep. We further developed a hippocampal-thalamocortical model to explain the mechanism underlying the duration and frequency-dependent coupling of thalamic spindles to hipp...

The NMDARs are key players in both physiological and pathologic synaptic plasticity because of their involvement in many aspects of neuronal transmission as well as learning and memory. The contribution in these events of different types of GluN2A-interacting proteins is still unclear. The p140Cap scaffold protein acts as a hub for postsynaptic complexes relevant to psychiatric and neurologic disorders and regulates synaptic functions, such as the stabilization of mature dendritic spine, memory consolidation, LTP, and LTD. Here we demonstrate that p140Cap directly binds the GluN2A subunit of NMDAR and modulates GluN2A-associated molecular network. Indeed, in p140Cap KO male mice, GluN2A is less associated with PSD95 both in ex vivo synaptosomes and in cultured hippocampal neurons, and p140Cap expression in KO neurons can rescue GluN2A and PSD95 colocalization. p140Cap is crucial in the recruitment of GluN2A-containing NMDARs and, consequently, in regulating NMDARs' intrinsic properties. p140Cap is associat...

Dorsal raphe (DR) 5-HT neurons regulate sleep–wake transitions. Previous studies demonstrated that single-unit activity of DR 5-HT neurons is high during wakefulness, decreases during non-rapid eye movement (NREM) sleep, and ceases during rapid eye movement (REM) sleep. However, characteristics of the population-level activity of DR 5-HT neurons, which influence the entire brain, are largely unknown. Here, we measured population activities of 5-HT neurons in the male and female mouse DR across the sleep–wake cycle by ratiometric fiber photometry. We found a slow oscillatory activity of compound intracellular Ca2+ signals during NREM sleep. The trough of the concave 5-HT activity increased across sleep progression, but 5-HT activity always returned to that seen during the wake period. When the trough reached a minimum and remained there, REM sleep was initiated. We also found a unique coupling of the oscillatory 5-HT activity and wideband EEG power fluctuation. Furthermore, optogenetic activation of 5-HT ne...

Costanza Angelini, Alessandro Morellato, Annalisa Alfieri, Lisa Pavinato, Tiziana Cravero, et al. (see pages [7183–7200][1]) The postsynaptic density (PSD) of excitatory synapses contains an extraordinary number of proteins, including AMPA and NMDA receptors, accessory proteins that regulate

The mitochondrial anchor syntaphilin (SNPH) is a key mitochondrial protein normally expressed in axons to maintain neuronal health by positioning mitochondria along axons for metabolic needs. However, in 2019 we discovered a novel form of excitotoxicity that results when SNPH is misplaced into neuronal dendrites in disease models. A key unanswered question about this SNPH excitotoxicity is the pathologic molecules that trigger misplacement or intrusion of SNPH into dendrites. Here, we identified two different classes of pathologic molecules that interact to trigger dendritic SNPH intrusion. Using primary hippocampal neuronal cultures from mice of either sex, we demonstrated that the pro-inflammatory cytokine IL-1β interacts with NMDA to trigger SNPH intrusion into dendrites. First, IL-1β and NMDA each individually triggers dendritic SNPH intrusion. Second, IL-1β and NMDA do not act independently but interact. Thus, blocking NMDAR by the antagonist MK-801 blocks IL-1β from triggering dendritic SNPH intrusio...

Task representations are critical for cognitive control and adaptive behavior. The hierarchical organization of task representations allows humans to maintain goals, integrate information across varying contexts, and select potential responses. In this study we characterized the structure and interactive dynamics of task representations that facilitate cognitive control. Human participants (both males and females) performed a hierarchical task that required them to select a response rule while considering the contingencies from different contextual inputs. By applying time- and frequency-resolved representational similarity analysis to human electroencephalography data, we characterized properties of task representations that are otherwise difficult to observe. We found that participants formed multiple representations of task-relevant contexts and features from the presented stimuli, beyond simple stimulus–response mappings. These disparate representations were hierarchically structured, with higher-order...

To what extent is the size of the BOLD response influenced by factors other than neural activity? In a reanalysis of three neuroimaging datasets (male and female human participants), we find large systematic inhomogeneities in the BOLD response magnitude in primary visual cortex (V1): stimulus-evoked BOLD responses, expressed in units of percent signal change, are up to 50% larger along the representation of the horizontal meridian than the vertical meridian. To assess whether this surprising effect can be interpreted as differences in local neural activity, we quantified several factors that potentially contribute to the size of the BOLD response. We find relationships between BOLD response magnitude and cortical thickness, curvature, depth, and macrovasculature. These relationships are consistently found across subjects and datasets and suggest that variation in BOLD response magnitudes across cortical locations reflects, in part, differences in anatomy and vascularization. To compensate for these factor...

Adaptive behavior requires the ability to appropriately react to action errors. Post-error slowing (PES) of response times is one of the most reliable phenomena in human behavior. It has been proposed that PES is partially achieved through inhibition of the motor system. However, there is no direct evidence for this link, or indeed, that the motor system is physiologically inhibited after errors altogether. Here, we used transcranial magnetic stimulation and electromyography to measure corticospinal excitability (CSE) across four experiments using a Simon task, in which female and male human participants sometimes committed errors. Errors were followed by reduced CSE at two different time points and in two different modes. Shortly after error commission (250 ms), CSE was broadly suppressed (i.e., even task-unrelated motor effectors were inhibited). During the preparation of the subsequent response, CSE was specifically reduced at task-relevant effectors only. This latter effect was directly related to PES,...

Conversion of astroglia into functional neurons has been considered a promising therapeutic strategy for neurodegenerative diseases. Recent studies reported that downregulation of the RNA binding protein, polypyrimidine tract-binding protein 1 (PTBP1), converts astrocytes into neurons in situ in multiple mouse brain regions, consequently improving pathologic phenotypes associated with Parkinson's disease, RGC loss, and aging. Here, we demonstrate that PTBP1 downregulation using an astrocyte-specific AAV-mediated shRNA system fails to convert hippocampal astrocytes into neurons in both male and female wild-type (WT) and β-amyloid (5×FAD) and tau (PS19) Alzheimer's disease (AD) mouse models and fails to reverse synaptic/cognitive deficits and AD-associated pathology in male mice. Similarly, PTBP1 downregulation cannot convert astrocytes into neurons in the striatum and substantia nigra in both male and female WT mice. Together, our study suggests that cell fate conversion strategy for neurodegenerative disea...