Neuroscience
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The velocity of impact between an object and the human head is a critical factor influencing brain injury outcomes but has not been explored in any detail in animal models. Here we provide a comprehensive overview of the interplay between impact velocity and injury severity in a well-established weight-drop impact acceleration (WDIA) model of diffuse brain injury in rodents. ⋯ There were impact velocity-dependent reductions in sensorimotor performance and in cortical depth-related depression of sensory cortex responses; however axonal injury (demonstrated by immunohistochemistry for β-amyloid precursor protein and neurofilament heavy-chain) was discernible only at the highest impact velocity. We conclude that the WDIA model is capable of producing graded axonal injury in a repeatable manner, and as such will prove useful in the study of the biomechanics, pathophysiology and potential treatment of diffuse axonal injury.
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Migraine attacks are typically described as unilateral, throbbing pain that is usually accompanied by nausea, vomiting, and exaggerated sensitivities to light, noise and smell. The headache phase of a migraine attack is mediated by activation of the trigeminovascular pathway; a nociceptive pathway that originates in the meninges and carries pain signals through meningeal nociceptors to the spinal trigeminal nucleus and from there to the cortex through relay neurons in the thalamus. Recent studies in our lab have identified a population of trigeminovascular neurons in the posterior (Po) and lateral posterior (LP) thalamic nuclei that may be involved in the perception of whole-body allodynia (abnormal skin sensitivity) and photophobia (abnormal sensitivity to light) during migraine. ⋯ Such injections yielded retrogradely labeled neurons in the nucleus of the diagonal band of Broca, the dopaminergic cells group A11/A13, the ventromedial and ventral tuberomammillary nuclei of the hypothalamus. We also found that some of these neurons contain acetylcholine, dopamine, cholecystokinin and histamine, respectively. Accordingly, we speculate that these forebrain/hypothalamic projections to Po and LP may play a role in those migraine attacks triggered by disrupted sleep, skipping meals and emotional reactions.
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D2 receptor null mutant (Drd2(-/-)) mice have altered responses to the rewarding and locomotor effects of psychostimulant drugs, which is evidence of a necessary role for D2 receptors in these behaviors. Furthermore, work with mice that constitutively express only the D2 receptor short form (D2S), as a result of genetic deletion of the long form (D2L), provides the basis for a current model in which D2L is thought to be the postsynaptic D2 receptor on medium spiny neurons in the basal forebrain, and D2S the autoreceptor that regulates the activity of dopamine neurons and dopamine synthesis and release. Because constitutive genetic deletion of the D2 or D2L receptor may cause compensatory changes that influence functional outcomes, our approach is to identify aspects of the abnormal phenotype of a Drd2(-/-) mouse that can be normalized by virus-mediated D2 receptor expression. ⋯ Furthermore, the effect of expression of D2S was indistinguishable from D2L. Similarly, virus-mediated expression of either D2S or D2L in substantia nigra neurons restored D2 agonist-induced activation of GIRKs. In this acute expression system, the alternatively spliced forms of the D2 receptor appear to be equally capable of acting as postsynaptic receptors and autoreceptors.
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In many day-to-day situations humans manifest a marked tendency to hold the head vertical while performing sensori-motor actions. For instance, when performing coordinated whole-body motor tasks, such as skiing, gymnastics or simply walking, and even when driving a car, human subjects will strive to keep the head aligned with the gravito-inertial vector. Until now, this phenomenon has been thought of as a means to limit variations of sensory signals emanating from the eyes and inner ears. ⋯ In this situation, the CNS might reconstruct the orientation of the target in kinesthetic space or reconstruct the orientation of the hand in visual space, or both. By having subjects tilt the head during target acquisition or during movement execution, we show a greater propensity to perform the sensory reconstruction that can be achieved when the head is held upright. These results suggest that the reason humans tend to keep their head upright may also have to do with how the brain manipulates and stores spatial information between reference frames and between sensory modalities, rather than only being tied to the specific problem of stabilizing visual and vestibular inputs.
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Neuronal differentiation, pathfinding and morphology are directed by biochemical cues that in vivo are presented in a complex scaffold of extracellular matrix. This microenvironment is three-dimensional (3D) and heterogeneous. Therefore, it is not surprising that more physiologically-relevant cellular responses are found in 3D culture environments rather than on two-dimensional (2D) flat substrates. ⋯ Rac and Rho expression are decreased in 3D vs 2D culture but not correlated with β1-integrin function. These results suggest that proper β1-integrin activity is required for the elaboration of physiologic DRG morphology and that 3D culture provides a more appropriate milieu to the mimic in vivo scenario. We propose that neuronal morphology may be directed during development and regeneration by factors that influence how β1-integrin, FAK and RhoGTPase molecules integrate substrate signals in the 3D microenvironment.