The physiological underpinnings of the necessity of sleep remain uncertain. Recent evidence suggests that sleep increases the convection of cerebrospinal fluid (CSF) and promotes the export of interstitial solutes, thus providing a framework to explain why all vertebrate species require sleep. Cardiovascular, respiratory and vasomotor brain pulsations have each been shown to drive CSF flow along perivascular spaces, yet it is unknown how such pulsations may change during sleep in humans. To investigate these pulsation phenomena in relation to sleep, we simultaneously recorded fast fMRI, magnetic resonance encephalography (MREG), and electroencephalography (EEG) signals in a group of healthy volunteers. We quantified sleep-related changes in the signal frequency distributions by spectral entropy analysis and calculated the strength of the physiological (vasomotor, respiratory, and cardiac) brain pulsations by power sum analysis in 15 subjects (age 26.5 ± 4.2 years, 6 females). Finally, we identified spatial...

Scaling between subcomponents of folding and total brain volume (TBV) in healthy individuals (HIs) is allometric. It is unclear whether this is true in schizophrenia (SZ) or first-episode psychosis (FEP). This study confirmed normative allometric scaling norms in HIs using discovery and replication samples. Cross-sectional and longitudinal diagnostic differences in folding subcomponents were then assessed using an allometric framework. Structural imaging from a longitudinal (Sample 1: HI and SZ, nHI Baseline = 298, nSZ Baseline = 169, nHI Follow-up = 293, nSZ Follow-up = 168, totaling 1087 images, all individuals ≥ 2 images, age 16-69 years) and a cross-sectional sample (Sample 2: nHI = 61 and nFEP = 89, age 10-30 years), all human males and females, is leveraged to calculate global folding and its nested subcomponents: sulcation index (SI, total sulcal/cortical hull area) and determinants of sulcal area: sulcal length and sulcal depth. Scaling of SI, sulcal area, and sulcal length with TBV in SZ and FEP w...

Network analyses inform complex systems such as human brain connectivity, but this approach is seldom applied to gold-standard histopathology. Here, we use two complimentary computational approaches to model microscopic progression of the main subtypes of tauopathy versus TDP-43 proteinopathy in the human brain. Digital histopathology measures were obtained in up to 13 gray matter (GM) and adjacent white matter (WM) cortical brain regions sampled from 53 tauopathy and 66 TDP-43 proteinopathy autopsy patients. First, we constructed a weighted non-directed graph for each group, where nodes are defined as GM and WM regions sampled and edges in the graph are weighted using the group-level Pearson’s correlation coefficient for each pairwise node comparison. Additionally, we performed mediation analyses to test mediation effects of WM pathology between anterior frontotemporal and posterior parietal GM nodes. We find greater correlation (i.e., edges) between GM and WM node pairs in tauopathies compared with TDP-4...

Cervical and trigeminal afferents innervate neighboring cranial territories, and their convergence on upper cervical dorsal horn neurons provides a potential substrate for pain referral in primary headache syndromes. Lamina I neurons are central to this mechanism as they relay convergent nociceptive input to supraspinal pain centers. Unfortunately, little is known about the interactions between trigeminal and cervical afferents supplying lamina I neurons. Here we used rats of both sexes to show that cervical and trigeminal afferents interact via presynaptic inhibition, where monosynaptic inputs to lamina I neurons undergo unidirectional as well as reciprocal presynaptic control. This means that afferent-driven presynaptic inhibition shapes the way trigeminal and cervical Aδ- and C-fiber input reaches lamina I projection and local-circuit neurons. We propose that this inhibition provides a feedforward control of excitatory drive to lamina I neurons that regulates their convergent and cervical- or trigeminal...

Metacognition describes the process of monitoring one’s own mental states, often for the purpose of cognitive control. Previous research has investigated how metacognitive signals are generated (metacognitive monitoring), for example when people (both f/m) judge their confidence in their decisions and memories. Research has also investigated how metacognitive signals are used to influence behavior (metacognitive control), for example setting a reminder (i.e. cognitive offloading ) for something you are not confident you will remember. However, the mapping between metacognitive monitoring and metacognitive control needs further study on a neural level. We used fMRI to investigate a delayed-intentions task with a reminder element, allowing human participants to use their metacognitive insight to engage metacognitive control. Using multivariate pattern analysis, we found that we could separately decode both monitoring and control, and, to a lesser extent, cross-classify between them. Therefore, brain patterns...

Traumatic spinal cord injury (SCI) above the major spinal sympathetic outflow (T6 level) disinhibits sympathetic neurons from supraspinal control, causing systems-wide ‘dysautonomia’. We recently showed that remarkable structural remodeling and plasticity occurs within spinal sympathetic circuitry, creating abnormal sympathetic reflexes that exacerbate dysautonomia over time. As an example, thoracic VGlut2+ spinal interneurons (SpINs) become structurally and functionally integrated with neurons that comprise the spinal-splenic sympathetic network and immunological dysfunction becomes progressively worse after SCI. To test whether the onset and progression of SCI-induced sympathetic plasticity is neuron activity-dependent, we selectively inhibited (or excited) thoracic VGlut2+ interneurons using chemogenetics. New data show that silencing VGlut2+ interneurons in female and male mice with a T3 SCI, using hM4Di-designer receptors exclusively activated by designer drugs (Gi DREADDs), blocks structural plastici...

Dynamic functional connectivity within brain circuits requires coordination of intercellular signaling and intracellular signal transduction. Critical roles for cAMP-dependent Protein Kinase A (PKA) signaling are well established in the Drosophila Mushroom Body (MB) learning and memory circuitry, but local PKA activity within this well-mapped neuronal network is uncharacterized. Here, we use an in vivo PKA activity sensor (PKA-SPARK) to test spatiotemporal regulatory requirements in the MB axon lobes. We find immature animals have little detectable PKA activity, whereas post-critical period adults show high field-selective activation primarily in just 3/16 defined output regions. In addition to the age-dependent PKA activity in distinct α’/β’ lobe nodes, females show sex-dependent elevation compared to males in these same restricted regions. Loss of neural cell body Fragile X Mental Retardation Protein (FMRP) and Rugose (human Neurobeachin) suppresses localized PKA activity, whereas over-expression of MB l...

Current methods to isolate synaptic vesicles (SVs), the organellar quanta of synaptic transmission, require highly specialized materials and up to 24 hours. These technical obstacles have thus far limited the study of SVs in models of synaptic function and pathophysiology. Here, we describe techniques for the rapid isolation of SVs by immunoprecipitation with widely available antibodies conjugated to magnetic beads. We report that the inexpensive rho1D4 monoclonal antibody binds SVs and show that elution with the 1D4 peptide yields native vesicles that are ≥ 10-fold purer than those obtained with classical techniques. These methods substantially widen the accessibility of SVs, enabling their purification in 60-90 minutes for downstream analyses including mass spectrometry and cryo-electron microscopy. Immunopurified SV preparations from mouse brain contained apolipoprotein E (ApoE), the low-density lipoprotein (LDL) receptor Lrp1, and enzymes involved in lipid metabolism, suggesting that SVs may play direc...

During sleep, the widespread coordination of neuronal oscillations across both cortical and subcortical brain regions is thought to support various physiological functions. However, how sleep-related activity within the brain's largest sensorimotor structure, the cerebellum, is multiplexed with well-described sleep-related mechanisms in regions such as the hippocampus remains unknown. We therefore simultaneously recorded from the dorsal hippocampus and three distinct regions of the cerebellum (Crus I, lobule VI, and lobules II/III) in male mice during natural sleep. Local field potential (LFP) oscillations were found to be coordinated between these structures in a sleep stage-specific manner. During non-REM sleep, prominent δ frequency coherence was observed between lobule VI and hippocampus, whereas non-REM-associated hippocampal sharp-wave ripple activity evoked discrete LFP modulation in all recorded cerebellar regions, with the shortest latency effects in lobule VI. We also describe discrete phasic sha...