Sleep-wake body temperature regulates tau secretion in mice and correlates with CSF and plasma tau in humans.

The sleep-wake cycle regulates interstitial fluid and cerebrospinal fluid (CSF) tau levels in both mouse and human by mechanisms that remain unestablished. Here, we reveal a novel pathway by which wakefulness increases extracellular tau levels in mouse and humans. In mice, higher body temperature (BT) associated with wakefulness and sleep deprivation increased CSF tau. In vitro, wakefulness temperatures upregulated tau secretion via a temperature-dependent increase in activity and expression of unconventional protein secretion pathway-1 components, namely caspase-3-mediated C-terminal cleavage of tau (TauC3), and membrane expression of PIP2 and syndecan-3. In humans, the increase in both CSF and plasma tau levels observed post-wakefulness correlated with BT increase during wakefulness. Our findings suggest sleep-wake variation in BT may contribute to regulating extracellular tau levels, highlighting the importance of thermoregulation in pathways linking sleep disturbance to neurodegeneration, and the potential for thermal intervention to prevent or delay tau-mediated neurodegeneration.

Movement-Related Modulation in Mouse Auditory Cortex Is Widespread Yet Locally Diverse.

Neurons in the mouse auditory cortex are strongly influenced by behavior, including both suppression and enhancement of sound-evoked responses during movement. The mouse auditory cortex comprises multiple fields with different roles in sound processing and distinct connectivity to movement-related centers of the brain. Here, we asked whether movement-related modulation in male mice might differ across auditory cortical fields, thereby contributing to the heterogeneity of movement-related modulation at the single-cell level. We used wide-field calcium imaging to identify distinct cortical fields and cellular-resolution two-photon calcium imaging to visualize the activity of layer 2/3 excitatory neurons within each field. We measured each neuron's responses to three sound categories (pure tones, chirps, and amplitude-modulated white noise) as mice rested and ran on a non-motorized treadmill. We found that individual neurons in each cortical field typically respond to just one sound category. Some neurons are only active during rest and others during locomotion, and those that are responsive across conditions retain their sound-category tuning. The effects of locomotion on sound-evoked responses vary at the single-cell level, with both suppression and enhancement of neural responses, and the net modulatory effect of locomotion is largely conserved across cortical fields. Movement-related modulation in auditory cortex also reflects more complex behavioral patterns, including instantaneous running speed and nonlocomotor movements such as grooming and postural adjustments, with similar patterns seen across all auditory cortical fields. Our findings underscore the complexity of movement-related modulation throughout the mouse auditory cortex and indicate that movement-related modulation is a widespread phenomenon.

Movement-related modulation in mouse auditory cortex is widespread yet locally diverse.

Neurons in the mouse auditory cortex are strongly influenced by behavior, including both suppression and enhancement of sound-evoked responses during movement. The mouse auditory cortex comprises multiple fields with different roles in sound processing and distinct connectivity to movement-related centers of the brain. Here, we asked whether movement-related modulation might differ across auditory cortical fields, thereby contributing to the heterogeneity of movement-related modulation at the single-cell level. We used wide-field calcium imaging to identify distinct cortical fields followed by cellular-resolution two-photon calcium imaging to visualize the activity of layer 2/3 excitatory neurons within each field. We measured each neuron's responses to three sound categories (pure tones, chirps, and amplitude modulated white noise) as mice rested and ran on a non-motorized treadmill. We found that individual neurons in each cortical field typically respond to just one sound category. Some neurons are only active during rest and others during locomotion, and those that are responsive across conditions retain their sound-category tuning. The effects of locomotion on sound-evoked responses vary at the single-cell level, with both suppression and enhancement of neural responses, and the net modulatory effect of locomotion is largely conserved across cortical fields. Movement-related modulation in auditory cortex also reflects more complex behavioral patterns, including instantaneous running speed and non-locomotor movements such as grooming and postural adjustments, with similar patterns seen across all auditory cortical fields. Our findings underscore the complexity of movement-related modulation throughout the mouse auditory cortex and indicate that movement-related modulation is a widespread phenomenon.

Evaluation of major depressive disorder using 7 Tesla phase sensitive neuroimaging before and after mindfulness-based cognitive therapy.

OBJECTIVE: We applied 7 Tesla phase sensitive imaging to evaluate the impact of brain iron levels on depression severity and cognitive function in individuals with major depressive disorder (MDD) treated with mindfulness-based cognitive therapy (MBCT). METHODS: Seventeen unmedicated MDD participants underwent MRI, evaluation of depression severity, and cognitive testing before and after receiving MBCT, compared to fourteen healthy controls (HC). Local field shift (LFS) values, measures of brain iron levels, were derived from phase images in the putamen, caudate, globus pallidus (GP), anterior cingulate cortex (ACC) and thalamus. RESULTS: Compared to the HC group, the MDD group had significantly lower baseline LFS (indicative of higher iron) in the left GP and left putamen and had a higher number of subjects with impairment in a test of information processing speed. In the MDD group, lower LFS values in the left and right ACC, right putamen, right GP, and right thalamus were significantly associated with depression severity; and lower LFS in the right GP was correlated with worse performance on measures of attention. All MBCT participants experienced depression relief. MBCT treatment also significantly improved executive function and attention. MBCT participants with lower baseline LFS values in the right caudate experienced significantly greater improvement in depression severity with treatment; and those with lower LFS values in the right ACC, right caudate, and right GB at baseline performed better on measures of verbal learning and memory after MBCT. CONCLUSIONS: Our study highlights the potential contribution of subtle differences in brain iron to MDD symptoms and their successful treatment.