The medial septum and diagonal band (MSDB) are important in spatial learning and memory. Based on excitotoxic damage of GABAergic MSDB neurons, we have recently suggested a role for these neurons in controlling proactive interference. The present study sought to test this hypothesis in different behavioral procedures using a new GABAergic immunotoxin. GAT1-saporin (GAT1-SAP) was administered into the MSDB of male Sprague Dawley rats. Following surgery, rats were trained in a reference memory water maze procedure for 5 days, followed by a working memory (delayed match to position) water maze procedure. Other rats were trained in a lever press avoidance procedure after intraseptal GAT1-SAP or sham surgery. Intraseptal GAT1-SAP produced extensive damage of GABAergic while sparing most cholinergic MSDB neurons. Rats treated with GAT1-SAP were not impaired in acquiring a spatial reference memory, learning the location of the escape platform as rapidly as sham rats. In contrast, GAT1-SAP rats were slower than sham rats to learn the platform location in a delayed match to position procedure, in which the platform location was changed every day. Moreover, GAT1-SAP rats returned to previous platform locations more often than sham rats. In the active avoidance procedure, intraseptal GAT1-SAP impaired extinction but not acquisition of the avoidance response. Using a different neurotoxin and behavioral procedures than previous studies, the results of the present study paint a similar picture that GABAergic MSDB neurons are important for controlling proactive interference. Keywordshippocampus; learning; memory; acetylcholine; basal forebrain; diagonal band of BrocaThe medial septum (MS) and diagonal band of Broca (DB) are major afferents to the hippocampus (Amaral and Kurz, 1985;Jakab and Leranth, 1995) and are critical for learning and memory (Kesner et al., 1986;Winson, 1978). Projections to the hippocampus arise mainly from cholinergic, GABAergic and glutamatergic neurons (Amaral and Kurz, 1985;Colom et al., 2005;Freund, 1989), and these projections may be important in the cognitive impairments associated with Alzheimer's Disease and normal aging (Bartus et al., 1982;Coyle et al., 1983). For example, damage or inactivation of the MSDB impairs performance

Acoustic startle response (ASR) is a defensive reflex that is largely ignored unless greatly exaggerated. ASR is suppressed after moderate and severe traumatic brain injury (TBI), but the effect of mild TBI (mTBI) on ASR has not been investigated. Because the neural circuitry for ASR resides in the pons in all mammals, ASR may be a good measure of brainstem function after mTBI. The present study assessed ASR in Sprague-Dawley rats after mTBI using lateral fluid percussion and compared these effects to those on spatial working memory. mTBI caused a profound, long-lasting suppression of ASR. Both probability of emitting a startle and startle amplitude were diminished. ASR suppression was observed as soon as 1 day after injury and remained suppressed for the duration of the study (21 days after injury). No indication of recovery was observed. mTBI also impaired spatial working memory. In contrast to the suppression of ASR, working memory impairment was transient; memory was impaired 1 and 7 days after injury, but recovered by 21 days. The long-lasting suppression of ASR suggests long-term dysfunction of brainstem neural circuits at a time when forebrain neural circuits responsible for spatial working memory have recovered. These results have important implications for return-to-activity decisions because recovery of cognitive impairments plays an important role in these decisions.

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Exposure to lateral fluid percussion (LFP) injury consistent with mild traumatic brain injury (mTBI) persistently attenuates acoustic startle responses (ASRs) in rats. Here, we examined whether the experience of head trauma affects stress reactivity. Male Sprague-Dawley rats were matched for ASRs and randomly assigned to receive mTBI through LFP or experience a sham surgery (SHAM). ASRs were measured post injury days (PIDs) 1, 3, 7, 14, 21, and 28. To assess neurosteroids, rats received a single 2.0 mA, 0.5 s foot shock on PID 34 (S34), PID 35 (S35), on both days (2S), or the experimental context (CON). Levels of the neurosteroids pregnenolone (PREG), allopregnanolone (ALLO), and androsterone (ANDRO) were determined for the prefrontal cortex, hippocampus, and cerebellum. For 2S rats, repeated blood samples were obtained at 15, 30, and 60 min post-stressor for determination of corticosterone (CORT) levels after stress or context on PID 34. Similar to earlier work, ASRs were severely attenuated in mTBI rats without remission for 28 days after injury. No differences were observed between mTBI and SHAM rats in basal CORT, peak CORT levels or its recovery. In serum and brain, ANDRO levels were the most stress-sensitive. Stress-induced ANDRO elevations were greater than those in mTBI rats. As a positive allosteric modulator of gamma-aminobutyric acid (GABAA) receptors, increased brain ANDRO levels are expected to be anxiolytic. The impact of brain ANDRO elevations in the aftermath of mTBI on coping warrants further elaboration.

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