Reversible behavioral deficits in rats during a cycle of demyelination-remyelination of the fimbria.

Traumatic brain injury (TBI) selectively damages white matter. White matter damage does not produce deficits in many behavioral tests used to analyze experimental TBI. Rats were impaired on an active place avoidance task following inactivation of one hippocampal injection of tetrodotoxin. The need for both hippocampi suggests that acquisition of the active place avoidance task may require interhippocampal communication. The controlled cortical impact model of TBI demyelinates midline white matter and impairs rats on the active place avoidance task. One white matter region that is demyelinated is the fimbria that contains hippocampal commissural fibers. We therefore tested whether demyelination of the fimbria produces deficits in active place avoidance. Lysophosphatidylcholine (LPC) was injected stereotaxically to produce a cycle of demyelination-remyelination of the fimbria. At 4 days, myelin loss was observed in the fimbria of LPC-, but not saline-injected rats. Fourteen days after injection, myelin content increased in LPC-, but not saline-injected rats. Three days after injection, both saline- and LPC-injected rats had similar performance on an open field and passive place avoidance task in which the rat avoided a stationary shock zone on a stationary arena. The following day, on the active place avoidance task, LPC-injected rats had a significantly higher number of shock zone entrances suggesting learning was impaired. At 14 days after injection, saline- and LPC-injected rats had similar performance on open field and passive place avoidance. On active place avoidance, however, saline- and LPC-injected rats had a similar number of total entrances suggesting that the impairment seen at 4 days was no longer present at 14 days. These data suggest that active place avoidance is highly sensitive to white matter injury

Behavioral analyses at times of demyelination and remyelination.

<p><b>Panel A,</b> Total distance traveled during active place avoidance. Rats injected with LPC or saline traveled a similar distance at both 4 and 14 days (F_(3,19)  = 1.71). <b>Panel B,</b> Representative tracks of rats 4 or 14 days after saline or LPC injection on the final (6^th) trial of active place avoidance. Red lines indicate the shock zone boundaries and the red circles indicate the locations where shocks were delivered. <b>Panel C,</b> Summary of the number of shock zone entrances in each trial of active place avoidance. At 4 days, saline- and LPC-injected animals showed a significant effect of treatment (F_(1,10)  = 16.31, p<0.005) and trial (F_(5,50)  = 4.20, p<0.005) with no interaction of treatment and trial (F_(5,50)  = 0.47). At 14 days, saline and LPC-injected animals had an no significant effect of treatment (F_(1,10)  = 0.23), but there was a significant effect of trial (F_(5,55)  = 5.81, p<0.001). Saline-treated animals analyzed at 4 and 14 days showed no significant effect of days (F_(1,12)  = 1.78), but there was a significant effect of trial (F_(5,60)  = 3.35, p<0.0005). LPC-injected rats at 4 and 14 days, trended toward an effect of days (F_(1,9)  = 4.0, p = 0.08) but had a significant effect of trial (F_(5,45)  = 10.4 p<0.0001) and a significant interaction of treatment and trial (F_(5,45)  =  2.62, p<0.05). These data suggest that saline-injected animals acquired the active place avoidance task at both 4 and 14 days, whereas LPC-injected animals acquired the task only at 14 days. Saline- and LPC-injected animals differed in their acquisition the task at 4, but not 14 days.</p

Measurements of rat behavior during open field, passive place avoidance and active place avoidance.

<p>Measurements of rat behavior during open field, passive place avoidance and active place avoidance.</p

Righting Reflex Predicts Long-Term Histological and Behavioral Outcomes in a Closed Head Model of Traumatic Brain Injury.

Blunt impact produces a heterogeneous brain injury in people and in animal models of traumatic brain injury. We report that a single closed head impact to adult C57/BL6 mice produced two injury syndromes (CHI-1 and CHI-2). CHI-1 mice spontaneously reinitiated breathing after injury while CHI-2 mice had prolonged apnea and regained breathing only after cardiopulmonary resuscitation and supplementation of 100% O2. The CHI-1 group significantly regained righting reflex more rapidly than the CHI-2 group. At 7 days post-injury, CHI-1, but not CHI-2 mice, acquired but had no long-term retention of an active place avoidance task. The behavioral deficits of CHI-1 and CHI-2 mice were retained one-month after the injury. CHI-1 mice had loss of hippocampal neurons and localized white matter injury at one month after injury. CHI-2 had a larger loss of hippocampal neurons and more widespread loss of myelin and axons. High-speed videos made during the injury were followed by assessment of breathing and righting reflex. These videos show that CHI-2 mice experienced a larger vertical g-force than CHI-1 mice. Time to regain righting reflex in CHI-2 mice significantly correlated with vertical g-force. Thus, physiological responses occurring immediately after injury can be valuable surrogate markers of subsequent behavioral and histological deficits