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...

Theta oscillations are key brain rhythm involved in memory formation, sensorimotor integration, and control of locomotion and behavioral states. Generation and spatiotemporal synchronization of theta oscillations rely on interactions between brain nuclei forming a large neural network, which includes pontine nucleus incertus (NI). Here we identified distinct populations of NI neurons, based on the relationship of their firing to hippocampal waves, with a special focus on theta oscillations, and the direction and type of interaction with the medial septum (MS) in male, urethane-anesthetized rats. By recording NI neuronal firing and hippocampal LFP, we described NI neurons that fire action potentials in a theta phase-independent or theta phase-locked and delta wave-independent or delta wave-locked manner. Among hippocampal activity-independent NI neurons, irregular, slow-firing, and regular, fast-firing cells were observed, while hippocampal oscillation-/wave-locked NI neurons were of a bursting or nonbursti...

Individuals with chronic pain often experience depression, resulting in greater disability and a worse prognosis than either condition alone ([Goesling et al., 2013][1]). The prevalence of depression among individuals experiencing neuropathic pain, one type of chronic pain caused by injury of the

Hemalatha Muralidharan, Shrobona Guha, Kiran Madugula, Ankita Patil, Sarah A. Bennison, et al. (see pages [2149–2165][1]) The first cells of the developing nervous system are radial glial cells, the progenitors of neurons and astrocytes. These elongated cells contact both the ventricular (apical

Spreading depolarizations (SDs) of gray matter occur in the brain in different pathologic conditions, and cause varying degrees of tissue damage depending on the extent of metabolic burden on the tissue. As might be expected for such large depolarizations, neurons exhibit bursts of action potentials (APs) as the wave propagates. However, the specific role of APs in SD propagation is unclear. This is potentially consequential, since sodium channel modulation has not been considered as a therapeutic target for SD-associated disorders, because of ambiguous experimental evidence. Using whole-cell electrophysiology and single-photon imaging in acute cortical slices from male C57Bl6 mice, we tested the effects of AP blockade on SDs generated by two widely used induction paradigms. We found that AP blockade using tetrodotoxin (TTX) restricted propagation of focally induced SDs, and significantly reduced the amplitude of neuronal depolarization, as well as its Ca2+ load. TTX also abolished the suppression of spont...

Brain function depends on segregation and integration of information processing in brain networks often separated by long-range anatomic connections. Neuronal oscillations orchestrate such distributed processing through transient amplitude and phase coupling, yet surprisingly, little is known about local network properties facilitating these functional connections. Here, we test whether criticality, a dynamical state characterized by scale-free oscillations, optimizes the capacity of neuronal networks to couple through amplitude or phase, and transfer information. We coupled in silico networks which exhibit oscillations in the α band (8–16 Hz), and varied excitatory and inhibitory connectivity. We found that phase coupling of oscillations emerges at criticality, and that amplitude coupling, as well as information transfer, are maximal when networks are critical. Importantly, regulating criticality through modulation of synaptic gain showed that critical dynamics, as opposed to a static ratio of excitatory ...