Enteric glia are a unique population of peripheral neuroglia that regulate homeostasis in the enteric nervous system (ENS) and intestinal functions. Despite existing in functionally diverse regions of the gastrointestinal tract, enteric glia have been approached scientifically as a homogenous group of cells. This assumption is at odds with the functional specializations of gastrointestinal organs and recent data suggesting glial heterogeneity in the brain and ENS. Here, we used calcium imaging in transgenic mice of both sexes expressing genetically encoded calcium sensors in enteric glia and conducted contractility studies to investigate functional diversity among myenteric glia in two functionally distinct intestinal organs: the duodenum and the colon. Our data show that myenteric glia exhibit regionally distinct responses to neuromodulators that require intercellular communication with neurons to differing extents in the duodenum and colon. Glia regulate intestinal contractility in a region- and pathway-...

Brain circuits are composed of diverse cell types with distinct morphologies, connections, and distributions of ion channels. Modeling suggests that the spatial distribution of the extracellular voltage during a spike depends on cellular morphology, connectivity, and identity. However, experimental evidence from the intact brain is lacking. Here, we combined high-density recordings from hippocampal region CA1 and neocortex of freely moving mice with optogenetic tagging of parvalbumin-immunoreactive (PV) cells. We used ground truth tagging of the recorded pyramidal cells (PYR) and PV cells to construct binary classification models. Features derived from single-channel waveforms or from spike timing alone allowed near-perfect classification of PYR and PV cells. To determine whether there is unique information in the spatial distribution of the extracellular potentials, we removed all single-channel waveform information from the multichannel waveforms using an event-based delta-transformation. We found that s...

Gonadotropin-releasing hormone (GnRH) neurons produce the final output from the brain to control pituitary gonadotropin secretion and thus regulate reproduction. Disruptions to gonadotropin secretion contribute to infertility, including polycystic ovary syndrome (PCOS) and idiopathic hypogonadotropic hypogonadism. PCOS is the leading cause of infertility in women and symptoms resembling PCOS are observed in girls at or near the time of pubertal onset, suggesting that alterations to the system likely occurred by that developmental period. Prenatally androgenized (PNA) female mice recapitulate many of the neuroendocrine phenotypes observed in PCOS, including altered time of puberty, disrupted reproductive cycles, increased circulating levels of testosterone, and altered gonadotropin secretion patterns. We tested the hypotheses that the intrinsic properties of GnRH neurons change with puberty and with PNA treatment. Whole-cell current-clamp recordings were made from GnRH neurons in brain slices from control a...

Retinal ganglion cell (RGC) axons comprise the optic nerve and carry information to the dorsolateral geniculate nucleus (dLGN), which is then relayed to the cortex for conscious vision. Glaucoma is a blinding neurodegenerative disease that commonly results from intraocular pressure (IOP)-associated injury leading to RGC axonal pathology, disruption of RGC outputs to the brain, and eventual apoptotic loss of RGC somata. The consequences of elevated IOP and glaucomatous pathology on RGC signaling to the dLGN are largely unknown yet are likely to contribute to vision loss. Here, we used anatomic and physiological approaches to study the structure and function of retinogeniculate (RG) synapses in male and female DBA/2J (D2) mice with inherited glaucoma before and after IOP elevation. D2 mice showed progressive loss of anterograde optic tract transport to the dLGN and vGlut2 labeling of RGC axon terminals while patch-clamp measurements of RG synaptic function showed that synaptic transmission was reduced in 9-m...

Mitochondrial dysfunction is one of the basic hallmarks of cellular pathology in neurodegenerative diseases. Since the metabolic activity of neurons is highly dependent on energy supply, nerve cells are especially vulnerable to impaired mitochondrial function. Besides providing oxidative phosphorylation, mitochondria are also involved in controlling levels of second messengers such as Ca2+ ions and reactive oxygen species (ROS). Interestingly, the critical role of mitochondria as producers of ROS is closely related to P2XR purinergic receptors, the activity of which is modulated by free radicals. Here, we review the relationships between the purinergic signaling system and affected mitochondrial function. Purinergic signaling regulates numerous vital biological processes in the CNS. The two main purines, ATP and adenosine, act as excitatory and inhibitory neurotransmitters, respectively. Current evidence suggests that purinergic signaling best explains how neuronal activity is related to neuronal electrica...

Understanding how the brain functions differently as one learns to read may shed light on the controversial nature of the reading ability of human being. Logographic writing system such as Chinese has been found to rely on specialized neural substrates beyond the reading network of alphabetic languages. The ability to read in Chinese has also been proposed to rely on writing skills. However, it was unclear whether the learning-related alteration of neural responses was language specific or resulted from the more reliance on writing practice during acquisition. This study investigated whether the emergence of typical logographic-specific regions relied on learning by writing. We taught proficient alphabetic language readers Chinese characters and used pre-test and post-test to identify changes in two critical stages of reading, namely, orthographic processing and orthographic-to-phonological mapping. Two typical left hemispheric areas for logographic reading showed increased responses to characters in the b...

Oligodendrocytes, the myelinating cells of the CNS, promote rapid action potential conduction along axons. Changes in the geometry of gaps between myelin segments, known as nodes of Ranvier, affect the conduction speed of neuronal impulses and can ultimately alter neural synchronization and circuit function. In contrast to synaptic plasticity, much less is known about how neural activity may affect node of Ranvier structure. Recently, perinodal astrocytes have been shown to remodel nodes of Ranvier by regulating thrombin proteolysis, but it is not known whether neural activity influences this process. To test this hypothesis, we used transgenic mice with astrocytic expression of a dominant-negative vesicle-associated membrane protein 2 ([gfap]dnVAMP2) to reduce exocytosis of thrombin inhibitors, modulating astrocytic regulation of paranodal loop attachment to induce nodal remodeling, under normal conditions and in adult mice maintained in darkness from postnatal day 40 (P40) to P70. This mechanism of nodal...

Coordinating the four limbs is an important feature of terrestrial mammalian locomotion. When the foot dorsum contacts an obstacle, cutaneous mechanoreceptors send afferent signals to the spinal cord to elicit coordinated reflex responses in the four limbs to ensure dynamic balance and forward progression. To determine how the locomotor pattern of all four limbs changes in response to a sensory perturbation evoked by activating cutaneous afferents from one hindlimb, we electrically stimulated the superficial peroneal (SP) nerve with a relatively long train at four different phases (mid-stance, stance-to-swing transition, mid-swing, and swing-to-stance transition) of the hindlimb cycle in seven adult cats. The largest functional effects of the stimulation were found at mid-swing and at the stance-to-swing transition with several changes in the ipsilateral hindlimb, such as increased activity in muscles that flex the knee and hip joints, increased joint flexion and toe height, increased stride/step lengths a...

Manipulating the activity of ventral tegmental area (VTA) dopamine (DA) neurons can drive nocifensive reflexes, and their firing rates are reduced following noxious stimuli. However, the pain-relevant inputs to the VTA remain incompletely understood. In this study, we used male and female mice in combination with identified dopamine and GABA neurons in the VTA that receive excitatory inputs from the periaqueductal gray (PAG), a nexus of ascending pain information. We tested whether PAG–VTA synapses undergo functional plasticity in response to a pain model using optical stimulation in conjunction with slice electrophysiology. We found that acute carrageenan inflammation does not significantly affect the strength of excitatory PAG synapses onto VTA DA neurons. However, at the PAG synapses on VTA GABA neurons, the subunit composition of NMDA receptors is altered; the complement of NR2D subunits at synaptic sites appears to be lost. Thus, our data support a model in which injury initially alters synapses on VT...

The importance of action–perception loops necessitates efficient computations linking motor and sensory systems. Corollary discharge (CD), a concept in motor-to-sensory transformation, has been proposed to predict the sensory consequences of actions for efficient motor and cognitive control. The predictive computation has been assumed to realize via inhibiting sensory reafference when actions are executed. Continuous control throughout the course of action demands inhibitory function ubiquitously on all potential reafference when sensory consequences are not available before execution. However, the temporal and functional characteristics of CD are unclear. When does CD begin to operate? To what extent does CD inhibit sensory processes? How is the inhibitory function implemented in neural computation? Using a delayed articulation paradigm with three types of auditory probes (speech, nonspeech, and nonhuman sounds) in an electroencephalography experiment with 20 human participants (7 males), we found that pr...