Uninterrupted in vivo cerebral microdialysis measures of the acute neurochemical response to a single or repeated concussion in a rat model combining force and rotation.

Altered extracellular amino acid concentrations following concussion or mild traumatic brain injury can result in delayed neuronal damage through overactivation of NMDA glutamatergic receptors. However, the consequences of repeated concussions prior to complete recovery are not well understood. In this study, we utilized in vivo cerebral microdialysis and a weight-drop model to investigate the acute neurochemical response to single and repeated concussions in adult rats that were fully conscious. A microdialysis probe was inserted into the hippocampus and remained in place during impact. Primary outcomes included concentrations of glutamate, GABA, taurine, glycine, glutamine, and serine, while secondary outcomes were righting times and excitotoxic indices. Compared to sham injury, the first concussion resulted in significant increases in glutamate, GABA, taurine, and glycine levels, longer righting times, and higher excitotoxic indices. Following the second concussion, righting times were significantly longer, suggesting cumulative effects of repeated concussion while only partial increases were observed in glutamate and taurine levels. GABA and glycine levels, and excitotoxic indices were comparable to sham injury. These findings suggest that single and repeated concussions may induce acute increases in several amino acids, while repeated concussions could exacerbate neurological symptoms despite less pronounced neurochemical changes.

Synaptotagmin-1-dependent phasic axonal dopamine release is dispensable for basic motor behaviors in mice.

In Parkinson's disease (PD), motor dysfunctions only become apparent after extensive loss of DA innervation. This resilience has been hypothesized to be due to the ability of many motor behaviors to be sustained through a diffuse basal tone of DA; but experimental evidence for this is limited. Here we show that conditional deletion of the calcium sensor synaptotagmin-1 (Syt1) in DA neurons (Syt1 cKODA mice) abrogates most activity-dependent axonal DA release in the striatum and mesencephalon, leaving somatodendritic (STD) DA release intact. Strikingly, Syt1 cKODA mice showed intact performance in multiple unconditioned DA-dependent motor tasks and even in a task evaluating conditioned motivation for food. Considering that basal extracellular DA levels in the striatum were unchanged, our findings suggest that activity-dependent DA release is dispensable for such tasks and that they can be sustained by a basal tone of extracellular DA. Taken together, our findings reveal the striking resilience of DA-dependent motor functions in the context of a near-abolition of phasic DA release, shedding new light on why extensive loss of DA innervation is required to reveal motor dysfunctions in PD.

Efficacy of prophylactic versus therapeutic administration of the NMDA receptor antagonist MK-801 on the acute neurochemical response to a concussion in a rat model combining force and rotation.

OBJECTIVE: Alterations in amino acid concentrations are a major contributor to the persistent neurological and behavioral effects induced by concussions and mild traumatic brain injuries (TBIs). Glutamate, the most abundant excitatory amino acid in the CNS, has a major role in the pathophysiological process of concussion. The indiscriminate liberation of glutamate immediately after a concussion triggers an excitotoxic response that leads to cell death, neuronal damage, and the dysfunction of surviving neurons, largely by overactivation of N-methyl-d-aspartate (NMDA) glutamatergic receptors. The aim of the present study was to investigate the efficacy of prophylactic versus therapeutic administration of MK-801, a promising NMDA receptor antagonist, on the acute changes in amino acid extracellular concentrations involved in excitotoxicity resulting from a concussive trauma. METHODS: The immediate neurochemical response to a concussion cannot be characterized in humans. Therefore, the authors used their previously validated combination of a weight-drop concussion rat model and in vivo cerebral microdialysis. The microdialysis probe was inserted inside the hippocampus and left inserted at impact to allow uninterrupted sampling of amino acids of interest immediately after concussion. The primary outcome included amino acid concentrations and the secondary outcome included righting time. Samples were taken in 10-minute increments for 60 minutes before, during, and 60 minutes after impact, and analyzed for glutamate, gamma-aminobutyric acid, taurine, glycine, glutamine, and serine using high-performance liquid chromatography. Righting time was acquired as a neurological restoration indicator. Physiological saline or 10 mg/kg MK-801 was administrated intraperitoneally 60 minutes before or immediately following induction of sham injury or concussion. RESULTS: Following induction of concussion, glutamate, taurine, and glycine levels as well as righting times in cases from the MK-801 treatment group were comparable to those of vehicle-treated animals. In contrast, righting times and amino acid concentrations observed within the first 10 minutes after induction of concussion in cases assigned to the MK-801 prophylaxis group were comparable to those of sham-injured animals. CONCLUSIONS: These results suggest that presynaptic actions and peak availability of MK-801 following prophylactic administration significantly inhibit the immediate and indiscriminate release of glutamate, taurine, and glycine in extracellular fluid after a concussion.

A Novel and Translational Rat Model of Concussion Combining Force and Rotation with In Vivo Cerebral Microdialysis.

Persistent cognitive and motor symptoms are known consequences of concussions/mild traumatic brain injury (mTBIs) that can be partly attributable to altered neurotransmission. Indeed, cerebral microdialysis studies in rodents have demonstrated an excessive extracellular glutamate release in the hippocampus within the first 10 min following trauma. Microdialysis offers the clear advantage of in vivo neurotransmitter continuous sampling while not having to sacrifice the animal. In addition to the aforementioned technique, a closed head injury model that exerts rapid acceleration and deceleration of the head and torso is needed, as such a factor is not available in many other animal models. The Wayne State weight-drop model mimics this essential component of human craniocerebral trauma, allowing the induction of an impact on the head of an unrestrained rodent with a falling weight. Our novel and translational rat model combines cerebral microdialysis with the Wayne State weight-drop model to study, in lightly anesthetized and unrestrained adult rats, the acute changes in extracellular neurotransmitter levels following concussion. In this protocol, the microdialysis probe was inserted inside the hippocampus as region of interest, and was left inserted in the brain at impact. There is a high density of terminals and receptors in the hippocampus, making it a relevant region to document altered neurotransmission following concussion. When applied to adult Sprague-Dawley rats, our combined model induced increases in hippocampal extracellular glutamate concentrations within the first 10 min, consistent with the previously reported post-concussion symptomology. This combined weight-drop model provides a reliable tool for researchers to study early therapeutic responses to concussions in addition to repetitive brain injury, since this protocol induces a closed-head mild trauma.

Asymmetric Direct Reciprocal Connections Between Primary Visual and Somatosensory Cortices of the Mouse.

Several studies show direct connections between primary sensory cortices involved in multisensory integration. The purpose of this study is to understand the microcircuitry of the reciprocal connections between visual and somatosensory cortices. The laminar distribution of retrogradely labeled cell bodies in V1 and in the somatosensory cortex both in (S1BF) and outside (S1) the barrel field was studied to provide layer indices in order to determine whether the connections are of feedforward, feedback or lateral type. Single axons were reconstructed and the size of their swellings was stereologically sampled. The negative layer indices in S1 and S1BF and the layer index near zero in V1 indicate that the connection from S1BF to V1 is of feedback type while the opposite is of lateral type. The greater incidence of larger axonal swellings in the projection from V1 to S1BF strongly suggests that S1BF receives a stronger driver input from V1 and that S1BF inputs to V1 have a predominant modulatory influence.

Strain differences of the effect of enucleation and anophthalmia on the size and growth of sensory cortices in mice.

Anophthalmia is a condition in which the eye does not develop from the early embryonic period. Early blindness induces cross-modal plastic modifications in the brain such as auditory and haptic activations of the visual cortex and also leads to a greater solicitation of the somatosensory and auditory cortices. The visual cortex is activated by auditory stimuli in anophthalmic mice and activity is known to alter the growth pattern of the cerebral cortex. The size of the primary visual, auditory and somatosensory cortices and of the corresponding specific sensory thalamic nuclei were measured in intact and enucleated C57Bl/6J mice and in ZRDCT anophthalmic mice (ZRDCT/An) to evaluate the contribution of cross-modal activity on the growth of the cerebral cortex. In addition, the size of these structures were compared in intact, enucleated and anophthalmic fourth generation backcrossed hybrid C57Bl/6J×ZRDCT/An mice to parse out the effects of mouse strains and of the different visual deprivations. The visual cortex was smaller in the anophthalmic ZRDCT/An than in the intact and enucleated C57Bl/6J mice. Also the auditory cortex was larger and the somatosensory cortex smaller in the ZRDCT/An than in the intact and enucleated C57Bl/6J mice. The size differences of sensory cortices between the enucleated and anophthalmic mice were no longer present in the hybrid mice, showing specific genetic differences between C57Bl/6J and ZRDCT mice. The post natal size increase of the visual cortex was less in the enucleated than in the anophthalmic and intact hybrid mice. This suggests differences in the activity of the visual cortex between enucleated and anophthalmic mice and that early in-utero spontaneous neural activity in the visual system contributes to the shaping of functional properties of cortical networks.