Blast-induced brain injury in rats leads to transient vestibulomotor deficits and persistent orofacial pain.

Blast-induced traumatic brain injury (blast-TBI) is associated with vestibulomotor dysfunction, persistent post-traumatic headaches and post-traumatic stress disorder, requiring extensive treatments and reducing quality-of-life. Treatment and prevention of these devastating outcomes require an understanding of their underlying pathophysiology through studies that take advantage of animal models. Here, we report that cranium-directed blast-TBI in rats results in signs of pain that last at least 8 weeks after injury. These occur without significantly elevated behavioural markers of anxiety-like conditions and are not associated with glial up-regulation in sensory thalamic nuclei. These injuries also produce transient vestibulomotor abnormalities that resolve within 3 weeks of injury. Thus, blast-TBI in rats recapitulates aspects of the human condition.

Roles of GABAA and GABAB receptors in regulating thalamic activity by the zona incerta: a computational study.

The posterior thalamic nucleus (PO) is a higher order nucleus heavily implicated in the processing of somatosensory information. We have previously shown in rodent models that activity in PO is tightly regulated by inhibitory inputs from a GABAergic nucleus known as the zona incerta (ZI). The level of incertal inhibition varies under both physiological and pathological conditions, leading to concomitant changes in PO activity. These changes are causally linked to variety of phenomena from altered sensory perception to pathological pain. ZI regulation of PO is mediated by GABAA and GABAB receptors (GABAAR and GABABR) that differ in their binding kinetics and their electrophysiological properties, suggesting that each may have distinct roles in incerto-thalamic regulation. We developed a computational model to test this hypothesis. We created a two-cell Hodgkin-Huxley model representing PO and ZI with kinetically realistic GABAAR- and GABABR-mediated synapses. We simulated spontaneous and evoked firing in PO and observed how these activities were affected by inhibition mediated by each receptor type. Our model predicts that spontaneous PO activity is preferentially regulated by GABABR-mediated mechanisms, while evoked activity is preferentially regulated by GABAAR. Our model also predicts that modulation of ZI firing rate and synaptic GABA concentrations is an effective means to regulate the incerto-thalamic circuit. The coupling of distinct functions to GABAAR and GABABR presents an opportunity for the development of therapeutics, as particular aspects of incerto-thalamic regulation can be targeted by manipulating the corresponding receptor class. Thus these findings may provide interventions for pathologies of sensory processing.

Intrinsic properties of and thalamocortical inputs onto identified corticothalamic-VPM neurons.

Corticothalamic (CT) feedback plays an important role in regulating the sensory information that the cortex receives. Within the somatosensory cortex layer VI originates the feedback to the ventral posterior medial (VPM) nucleus of the thalamus, which in turn receives sensory information from the contralateral whiskers. We examined the physiology and morphology of CT neurons in rat somatosensory cortex, focusing on the physiological characteristics of the monosynaptic inputs that they receive from the thalamus. To identify CT neurons, rhodamine microspheres were injected into VPM and allowed to retrogradely transport to the soma of CT neurons. Thalamocortical slices were prepared at least 3 days post injection. Whole-cell recordings from labeled CT cells in layer VI demonstrated that they are regular spiking neurons and exhibit little spike frequency adaption. Two anatomical classes were identified based on their apical dendrites that either terminated by layer V (compact cells) or layer IV (elaborate cells). Thalamic inputs onto identified CT-VPM neurons demonstrated paired pulse depression over a wide frequency range (2-20 Hz). Stimulus trains also resulted in significant synaptic depression above 10 Hz. Our results suggest that thalamic inputs differentially impact CT-VPM neurons in layer VI. This characteristic may allow them to differentiate a wide range of stimulation frequencies which in turn further tune the feedback signals to the thalamus.

Chronic pain following spinal cord injury.

Most patients with insults to the spinal cord or central nervous system suffer from excruciating, unrelenting, chronic pain that is largely resistant to treatment. This condition affects a large percentage of spinal cord injury patients, and numerous patients with multiple sclerosis, stroke and other conditions. Despite the recent advances in basic science and clinical research the pathophysiological mechanisms of pain following spinal cord injury remain unknown. Here we describe a novel mechanism of loss of inhibition within the thalamus that may predispose for the development of this chronic pain and discuss a potential treatment that may restore inhibition and ameliorate pain.

Zona incerta: a role in central pain.

Central pain syndrome (CPS) is a debilitating condition that affects a large number of patients with a primary lesion or dysfunction in the CNS. Despite its discovery over a century ago, the pathophysiological processes underlying the development and maintenance of CPS are poorly understood. We recently demonstrated that activity in the posterior thalamus (PO) is tightly regulated by inhibitory inputs from zona incerta (ZI). Here we test the hypothesis that CPS is associated with abnormal inhibitory regulation of PO by ZI. We recorded single units from ZI and PO in animals with CPS resulting from spinal cord lesions. Consistent with our hypothesis, the spontaneous firing rate and somatosensory evoked responses of ZI neurons were lower in lesioned animals compared with sham-operated controls. In PO, neurons recorded from lesioned rats exhibited significantly higher spontaneous firing rates and greater responses to noxious and innocuous stimuli applied to the hindpaw and to the face. These changes were not associated with increased afferent drive from the spinal trigeminal nucleus or changes in the ventroposterior thalamus. Thus CPS can result from suppressed inputs from the inhibitory nucleus zona incerta to the posterior thalamus.

The role of thalamic inputs in surround receptive fields of barrel neurons.

Controversy exists regarding the relative roles of thalamic versus intracortical inputs in shaping the response properties of cortical neurons. In the whisker-barrel system, this controversy centers on the mechanisms determining the receptive fields of layer IV (barrel) neurons. Whereas principal whisker-evoked responses are determined by thalamic inputs, the mechanisms responsible for adjacent whisker (AW) responses are in dispute. Here, we took advantage of the fact that lesions of the spinal trigeminal nucleus interpolaris (SpVi) significantly reduce the receptive field size of neurons in the ventroposterior thalamus. We reasoned that if AW responses are established by these thalamic inputs, brainstem lesions would significantly reduce the receptive field sizes of barrel neurons. We obtained extracellular single unit recordings from barrel neurons in response to whisker deflections from control rats and from rats that sustained SpVi lesions. After SpVi lesions, the receptive field of both excitatory and inhibitory barrel neurons decreased significantly in size, whereas offset/onset response ratios increased. Response magnitude decreased only for inhibitory neurons. All of these findings are consistent with the hypothesis that AW responses are determined primarily by direct thalamic inputs and not by intracortical interactions.

Functional circuitry involved in the regulation of whisker movements.

Neuroanatomical tract-tracing methods were used to identify the oligosynaptic circuitry by which the whisker representation of the motor cortex (wMCx) influences the facial motoneurons that control whisking activity (wFMNs). Injections of the retrograde tracer cholera toxin subunit B into physiologically identified wFMNs in the lateral facial nucleus resulted in dense, bilateral labeling throughout the brainstem reticular formation and in the ambiguus nucleus as well as predominantly ipsilateral labeling in the paralemniscal, pedunculopontine tegmental, Kölliker-Fuse, and parabrachial nuclei. In addition, neurons in the following midbrain regions projected to the wFMNs: superior colliculus, red nucleus, periaqueductal gray, mesencephalon, pons, and several nuclei involved in oculomotor behaviors. Injections of the anterograde tracer biotinylated dextran amine into the wMCx revealed direct projections to the brainstem reticular formation as well as multiple brainstem and midbrain structures shown to project to the wFMNs. Regions in which retrograde labeling and anterograde labeling overlap most extensively include the brainstem parvocellular, gigantocellular, intermediate, and medullary (dorsal and ventral) reticular formations; ambiguus nucleus; and midbrain superior colliculus and deep mesencephalic nucleus. Other regions that contain less dense regions of combined anterograde and retrograde labeling include the following nuclei: the interstitial nucleus of medial longitudinal fasciculus, the pontine reticular formation, and the lateral periaqueductal gray. Premotoneurons that receive dense inputs from the wMCx are likely to be important mediators of cortical regulation of whisker movements and may be a key component in a central pattern generator involved in the generation of rhythmic whisking activity.