This project reflects a longstanding interest in neural events that influence recovery and maintenance of function after brain damage. The major proposed experiments derive from recent work showing that a postoperative regimen of diazepam (Valium), at an anticonvulsant dose, disrupts recovery from the sensorimotor asymmetry that follows unilateral damage to neocortex in rats, and that the chemoconvulsant, pentylenetetrazole, facilitates recovery. Further analysis of diazepam and pentylenetetrazole will be carried out. Also, because diazepam is a GABA agonist, muscimol or bicuculline will be used to activate or block GABAergic receptors following brain damage. Rats will sustain unilateral cortical or striatal lesions, and recovery will be assessed with somatosensory tests, including an analog of the """"""""double simultaneous extinction"""""""" exam used in clinical neurology. The dosage, onset, and duration of the drug regimens will be manipulated. In most experiments, the agents will be infused intracranially. For example, in an effort to distinguish the role of seizures from that of GABA antagonism, bicuculline will be delivered to the prepiriform cortex, either in the hemisphere ipsilateral or contralateral to unilateral lesions of the somatosensory cortex. Seizures are expected to occur bilaterally, while GABA antagonism would be unilateral. Another study will use rats depleted of dopamine (via neonatal 6-OHDA) to explore in a preliminary way the role of nigrostriatal projections in recovery from cortical lesions and in the disruptive effects of diazepam on recovery. In a related experiments, muscimol will be infused intraventricularly following unilateral ibotenic acid (axon sparing) lesions in the striatum, which destroys striatonigral GABAergic neurons. A recent study found that muscimol prevents the transynaptic degeneration of cells in the substantia nigra, presumably by mimicking GABA. It has been argued that GABA agonists might therefore be beneficial to brain damaged people. However, it is possible that the effects of GABA agonists on recovery differ dramatically depending on the neurochemical circuitry of the brain regions damaged. Thus, GABA is not the predominant transmitter in neocortical projections. On the other hand, behavioral studies have yet to be carried out. Pilot work indicates that sensorimotor recovery after striatal lesions is correlated with the loss of nigra cells. Perhaps sensorimotor impairment is associated with the disinhibition of nigra cells, and transynaptic degeneration actually contributes to behavioral recovery. If so, then muscimol might retard, rather than facilitate, the return of sensorimotor symmetry after striatal lesions, as diazepam does when it is administered after neocortical lesions. These issues may be important clinically because the cortex is frequently affected in head injury and because diazepam and other anticonvulsant drugs that affect the GABA receptor have been used to prevent post-traumatic seizures.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS023964-05
Application #
3408124
Study Section
Biopsychology Study Section (BPO)
Project Start
1986-08-01
Project End
1992-07-31
Budget Start
1990-08-01
Budget End
1991-07-31
Support Year
5
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Texas Austin
Department
Type
Schools of Arts and Sciences
DUNS #
City
Austin
State
TX
Country
United States
Zip Code
78712
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Humm, J L; Kozlowski, D A; Bland, S T et al. (1999) Use-dependent exaggeration of brain injury: is glutamate involved? Exp Neurol 157:349-58
Bland, S T; Gonzale, R A; Schallert, T (1999) Movement-related glutamate levels in rat hippocampus, striatum, and sensorimotor cortex. Neurosci Lett 277:119-22
Kozlowski, D A; Schallert, T (1998) Relationship between dendritic pruning and behavioral recovery following sensorimotor cortex lesions. Behav Brain Res 97:89-98
Kozlowski, D A; Hilliard, S; Schallert, T (1997) Ethanol consumption following recovery from unilateral damage to the forelimb area of the sensorimotor cortex: reinstatement of deficits and prevention of dendritic pruning. Brain Res 763:159-66
Kozlowski, D A; James, D C; Schallert, T (1996) Use-dependent exaggeration of neuronal injury after unilateral sensorimotor cortex lesions. J Neurosci 16:4776-86
Jones, T A; Schallert, T (1994) Use-dependent growth of pyramidal neurons after neocortical damage. J Neurosci 14:2140-52
Schallert, T; Jones, T A (1993) ""Exuberant"" neuronal growth after brain damage in adult rats: the essential role of behavioral experience. J Neural Transplant Plast 4:193-8
Hall, S; Rutledge, J N; Schallert, T (1992) MRI, brain iron and experimental Parkinson's disease. J Neurol Sci 113:198-208
Jones, T A; Schallert, T (1992) Overgrowth and pruning of dendrites in adult rats recovering from neocortical damage. Brain Res 581:156-60

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