Neurogenesis persists throughout life in the neurogenic regions of the mature mammalian brain, and this response is enhanced after traumatic brain injury (TBI). In the hippocampus, adult neurogenesis plays an important role in hippocampal-dependent learning and memory functions and is thought to contribute to the spontaneous cognitive recovery observed after TBI. Utilizing an antimitotic agent, arabinofuranosyl cytidine (Ara-C), the current study investigated the direct association of injury-induced hippocampal neurogenesis with cognitive recovery. In this study, adult rats received a moderate lateral fluid percussion injury followed by a 7-day intraventricular infusion of 2% Ara-C or vehicle. To examine the effect of Ara-C on cell proliferation, animals received intraperitoneal injections of 5-bromo-2-deoxyuridine (BrdU), to label dividing cells, and were sacrificed at 7 days after injury. Brain sections were immunostained for BrdU or doublecortin (DCX), and the total number of BrdU(+) or DCX(+) cells in the hippocampus was quantified. To examine the outcome of inhibiting the injury-induced cell proliferative response on cognitive recovery, animals were assessed on Morris water maze (MWM) tasks at 21-25 or 56-60 days postinjury. We found that a 7-day infusion of Ara-C significantly reduced the total number of BrdU(+) and DCX(+) cells in the dentate gyrus (DG) in both hemispheres. Moreover, inhibition of the injury-induced cell proliferative response in the DG completely abolished the innate cognitive recovery on MWM performance at 56-60 days postinjury. These results support the causal relationship of injury-induced hippocampal neurogenesis on cognitive functional recovery and suggest the importance of this endogenous repair mechanism on restoration of hippocampal function.

Four pigeons were trained to discriminate between four stimuli. There were three stimuli correlated with reinforced responding and one stimulus correlated with nonreinforced responding. Stimuli were compounds of form (either square or triangle) and background color (either red or green) projected on the response key. Compound stimuli were constructed in such a way that some components of the form-color compound stimulus were more frequently associated with reinforced responding than other components. Results showed that the compound stimulus formed of components most frequently associated with reinforced responding did not consistently control a higher response rate than other stimuli less frequently associated with reinforcement. This finding raises the question of the importance of the stimulus restrictions placed on the investigation of the response summation phenomenon.

Three experiments were performed to determine the effects of schedule of reinforcement on additive summation using pigeons as subjects. In the first experiment the subjects were reinforced on a VI 1-min schedule whenever either of two stimuli was present. Their simultaneous presentation produced response summation. In the second experiment key color and the schedule of reinforcement were changed in alternate sessions. When the reinforcement schedule was VI 30 sec, only one of the four subjects showed response summation. When the reinforcement schedule was VI 3 min, all four subjects showed response summation. In the third experiment, the subjects were reinforced on a VI 30-sec schedule whenever either of two stimuli was present. Their simultaneous presentation produced response summation in only one of three subjects. The results suggest that either high reinforcement frequency or high response rate sets a ceiling beyond which response summation is not observed.

Traumatic axonal injury (TAI) is a major feature of traumatic brain injury (TBI) and is associated with much of its morbidity. To date, significant insight has been gained into the initiating pathogenesis of TAI. However, the nature of TAI within the injured brain precludes the consistent evaluation of its specific anterograde and retrograde sequelae. To overcome this limitation, we used the relatively organized optic nerve in a central fluid percussion injury (cFPI) model. To improve the visualization of TAI, we utilized mice expressing yellow fluorescent protein (YFP) in their visual pathways. Through this approach, we consistently generated TAI in the optic nerve and qualitatively and quantitatively evaluated its progression over a 48-h period in YFP axons via confocal microscopy and electron microscopy. In this model, delayed axonal swelling with subsequent disconnection were the norm, together with the fact that once disconnected, both the proximal and distal axonal segments revealed significant dieback, with the proximal swellings showing regression and reorganization, while the distal swellings persisted, although showing signs of impending degeneration. When antibodies targeting the C-terminus of amyloid precursor protein (APP), a routine marker of TAI were employed, they mapped exclusively to the proximal axonal segments without distal targeting, regardless of the survival time. Concomitant with this evolving axonal pathology, focal YFP fluorescence quenching occurred and mapped precisely to immunoreactive loci positive for Texas-Red-conjugated-IgG, indicating that blood-brain barrier disruption and its attendant edema contributed to this phenomenon. This was confirmed through the use of antibodies targeting endogenous YFP, which demonstrated the retention of intact immunoreactive axons despite YFP fluorescence quenching. Collectively, the results of this study within the injured optic nerve provide unprecedented insight into the evolving pathobiology associated with TAI.

Excitatory amino acid release and subsequent biochemical cascades following traumatic brain injury (TBI) have been well documented, especially glutamate-related excitotoxicity. The effects of TBI on the essential functions of inhibitory GABA-A receptors, however, are poorly understood.

Epidermal growth factor (EGF) is a known mitogen for neural stem and progenitor cells (NS/NPCs) in the central nervous system (CNS). In vitro, EGF maintains NS/NPCs in the proliferative state, whereas in the normal rodent brain it promotes their proliferation and migration in the subventricular zone (SVZ). Additionally, EGF administration can augment neuronal replacement in the ischemic-injured adult striatum. Recently we found that the SVZ and the hippocampus display an injury-induced proliferative response following traumatic brain injury (TBI) that is linked to increased EGF expression. As adult neurogenesis is associated with cognitive function, we hypothesized that post-TBI administration of EGF could affect neurogenesis and cognitive recovery. Adult rats were intraventricularly infused with EGF or vehicle for 7 days following TBI. 5-Bromo-2-deoxyuridine (BrdU) was administered to label proliferating cells and the animals were sacrificed at 1 or 4 weeks post-injury. Using immunohistochemistry and stereology, we found that at 1 week post-injury, compared to vehicle-infused animals EGF-infused animals had significantly more BrdU-positive cells in the SVZ and hippocampus concomitant with enhanced EGF receptor expression. At 4 weeks post-injury, the number of BrdU-positive cells in the hippocampus was similar in both groups, suggesting that EGF does not support long-term survival of newly generated cells. Furthermore, we found that the EGF-induced proliferative population differentiated preferentially toward astroglial phenotype. Nevertheless, animals treated with EGF showed significant improvement in cognitive function, which was accompanied by reduced hippocampal neuronal cell loss. Collectively, the data from this study demonstrate that EGF exerts a neuroprotective rather than neurogenic effect in protecting the brain from injury.

Traumatic brain injury (TBI) has been demonstrated to induce cerebral vascular dysfunction that is reflected in altered responses to various vasodilators. While previous reports have focused primarily on the short-term vascular alterations, few have examined these vascular changes for more than 7 days, or have attempted to correlate these alterations with any persisting behavioral changes or potential therapeutic modulation. Accordingly, we evaluated the long-term microvascular and behavioral consequences of experimental TBI and their therapeutic modulation via hypothermia. In this study, one group was injured with no treatment, another group was injured and 1 h later was treated with 120 min of hypothermia followed by slow rewarming, and a third group was non-injured. Animals equipped with cranial windows for visualization of the pial microvasculature were challenged with various vasodilators, including acetylcholine, hypercapnia, adenosine, pinacidil, and sodium nitroprusside, at either 1 or 3 weeks post-TBI. In addition, all animals were tested for vestibulomotor tasks at 1 week post-TBI, and animals surviving for 3 weeks post-TBI were tested in a Morris water maze (MWM). The results of this investigation demonstrated that TBI resulted in long-term vascular dysfunction in terms of altered vascular reactivity to various vasodilators, which was significantly improved with the use of a delayed 120-min hypothermic treatment. In contrast, data from the MWM task indicated that injured animals revealed persistent deficits in the spatial memory test performance, with hypothermia exerting no protective effects. Collectively, these data illustrate that TBI can evoke long-standing brain vascular and spatial memory dysfunction that manifest different responses to hypothermic intervention. These findings further illustrate the complexity of TBI and highlight the fact that the chosen hypothermic intervention may not necessarily exert a global protective response.

Stem/progenitor cells reside throughout the adult CNS and are actively dividing in the subventricular zone (SVZ) and the dentate gyrus (DG) of the hippocampus. This neurogenic capacity of the SVZ and DG is enhanced following traumatic brain injury (TBI) suggesting that the adult brain has the inherent potential to restore populations lost to injury. This raises the possibility of developing strategies aimed at harnessing the neurogenic capacity of these regions to repair the damaged brain. One strategy is to enhance neurogenesis with mitogenic factors. As basic fibroblast growth factor (bFGF) is a potent stem cell mitogen, we set out to determine if an intraventricular administration of bFGF following TBI could affect the levels of injury-induced neurogenesis in the SVZ and DG, and the degree to which this is associated with cognitive recovery. Specifically, adult rats received a bFGF intraventricular infusion for 7 days immediately following TBI. BrdU was administered to animals daily at 2-7 days post-injury to label cell proliferation. At 1 or 4 weeks post-injury, brain sections were immunostained for BrdU and neuronal or astrocytic markers. We found that injured animals infused with bFGF exhibited significantly enhanced cell proliferation in the SVZ and the DG at 1 week post-TBI as compared to vehicle-infused animals. Moreover, following bFGF infusion, a greater number of the newly generated cells survived to 4 weeks post-injury, with the majority being neurons. Additionally, animals infused with bFGF showed significant cognitive improvement. Collectively, the current findings suggest that bFGF-enhanced neurogenesis contributes to cognitive recovery following TBI.

Experimental traumatic brain injury (TBI) results in marked neurochemical and metabolic changes. Research has demonstrated that after the initial insult the brain undergoes an immediate state of hypermetabolism followed by a sustained period of hypometabolism. The altered extra- and intracellular environment can compromise neuronal performance and limit functional recovery. If brain metabolism is depressed chronically after TBI, then interventions that are designed to increase metabolism may be beneficial to outcome. Glucose treatment has been shown to improve cognition in many populations, particularly those with cognitive deficits. The following experiments examined the effects of delayed postinjury glucose supplementation on cognitive function following TBI. Male Sprague–Dawley rats received either sham or lateral fluid-percussion (LFP) injury. Cognitive functioning was assessed with the Morris water maze (MWM) on postinjury days 11–15. In the first experiment, saline or 100mg/kg glucose was administered 10min before cognition assessment. Injured animals treated with glucose displayed significantly shorter latencies to reach the goal platform compared to injured saline-treated animals. Glucose had no effect on sham-injured rats. In the second experiment, injured rats were given daily injections of saline or 100mg/kg glucose for 10 days beginning 24h after injury. Rats were then tested in the MWM on days 11–15 without glucose or saline treatment. In this experiment, glucose treatment did not affect MWM performance. These data provide evidence that the chronic energy supplementation after TBI improves outcome when administered shortly before cognitive assessment.

Catecholaminergic neurotransmission is regionally altered following injury, and drugs aimed at these systems offer promising avenues for post - traumatic brain injury ( TBI) pharmacotherapies. Atomoxetine is a selective norepinephrine transporter ( NET) inhibitor currently indicated for treatment of attention-deficit hyperactivity disorder ( ADHD). The current study was designed to test the efficacy of atomoxetine in treating cognitive deficits following experimental TBI in animals and to determine an optimal dose and therapeutic window for drug treatment. Sprague-Dawley rats were subjected to lateral fluid-percussion injury ( L-FPI) of moderate severity ( 2.08 atm +/- 0.05). Two experiments were performed. In the first study, atomoxetine ( 0.3, 1, 3, or 9 mg/ kg) or vehicle was administered daily on post-injury days ( PID) 1 - 15. Cognitive assessment was performed using the Morris water maze on PID 11 - 15. L-FPI resulted in significant cognitive impairment when compared to Sham-Injury. Treatment with lower doses of atomoxetine ( 0.3, 1, and 3 mg/ kg) significantly attenuated the cognitive deficits in injured animals. Treatment with the higher dosage ( 9 mg/ kg) of atomoxetine resulted in animals that were not significantly different than injured-vehicle treated animals. The optimal response was achieved using 1 mg/ kg atomoxetine. In the second study, treatment with atomoxetine ( 1 mg/ kg) or vehicle was delayed for 11 days post-injury. Rats were administered atomoxetine daily for 15 days, and cognitive assessment was performed on PID 25 - 29. In this study, treatment with atomoxetine ( 1 mg/ kg) did not result in improved cognitive performance. In conclusion, this is the first study to show low-dose atomoxetine initiated early after experimental TBI results in improved cognition.

Traumatic brain injury (TBI) survivors often suffer chronically from significant morbidity associated with cognitive deficits, behavioral difficulties and a post-traumatic syndrome and thus it is important to understand the pathophysiology of these long-term plasticity changes after TBI. Calcium (Ca2+) has been implicated in the pathophysiology of TBI-induced neuronal death and other forms of brain injury including stroke and status epilepticus. However, the potential role of long-term changes in neuronal Ca2+ dynamics after TBI has not been evaluated. In the present study, we measured basal free intracellular Ca2+ concentration ([Ca2+](i)) in acutely isolated CA3 hippocampal neurons from Sprague-Dawley rats at 1, 7 and 30 days after moderate central fluid percussion injury. Basal [Ca2+](i) was significantly elevated when measured 1 and 7 days post-TBI without evidence of neuronal death. Basal [Ca2+](i) returned to normal when measured 30 days post-TBI. In contrast, abnormalities in Ca2+ homeostasis were found for as long as 30 days after TBI. Studies evaluating the mechanisms underlying the altered Ca2+ homeostasis in TBI neurons indicated that necrotic or apoptotic cell death and abnormalities in Ca2+ influx and efflux mechanisms could not account for these changes and suggested that long-term changes in Ca2+ buffering or Ca2+ sequestration/release mechanisms underlie these changes in Ca2+ homeostasis after TBI. Further elucidation of the mechanisms of altered Ca2+ homeostasis in traumatized, surviving neurons in TBI may offer novel therapeutic interventions that may contribute to the treatment and relief of some of the morbidity associated with TBI.

Traumatic brain injury (TBI) survivors often suffer from a post-traumatic syndrome with deficits in learning and memory. Calcium (Ca2+) has been implicated in the pathophysiology of TBI-induced neuronal death. However, the role of long-term changes in neuronal Ca2+ function in surviving neurons and the potential impact on TBI-induced cognitive impairments are less understood. Here we evaluated neuronal death and basal free intracellular Ca2+ ([Ca2+]i) in acutely isolated rat CA3 hippocampal neurons using the Ca2+ indicator, Fura-2, at seven and thirty days after moderate central fluid percussion injury. In moderate TBI, cognitive deficits as evaluated by the Morris Water Maze (MWM), occur after injury but resolve after several weeks. Using MWM paradigm we compared alterations in [Ca2+]i and cognitive deficits. Moderate TBI did not cause significant hippocampal neuronal death. However, basal [Ca2+]i was significantly elevated when measured seven days post-TBI. At the same time, these animals exhibited significant cognitive impairment (F2,25 = 3.43, p < 0.05). When measured 30 days post-TBI, both basal [Ca2+]i and cognitive functions had returned to normal. Pretreatment with MK-801 blocked this elevation in [Ca2+]i and also prevented MWM deficits. These studies provide evidence for a link between elevated [Ca2+]i and altered cognition. Since no significant neuronal death was observed, the alterations in Ca2+ homeostasis in the traumatized, but surviving neurons may play a role in the pathophysiology of cognitive deficits that manifest in the acute setting after TBI and represent a novel target for therapeutic intervention following TBI.

Memory impairment is common following traumatic brain injury. However, the specific processes underlying the impairments remain unknown. Traumatic brain injury may interfere with several of the stages of the learning and memory process. In two separate experiments, we examined the specific nature of both anterograde and retrograde memory dysfunction following fluid percussion brain injury in rats. In Experiment 1, we examined the retention of spatial memory in the MWM after equating initial learning between sham and injured animals. Animals were trained to criterion and then tested for retention 4, 8, or 24 h post-training. Although injured animals displayed deficits in task acquisition, retention performance was not significantly different between groups. In Experiment 2, we examined the effects of injury on the retention of retrograde spatial memories in the MWM. Animals were injured either 1 or 14 days post-training and then received retention probe trials followed by a reminding procedure and second probe trial 14 days post-injury. All injured animals displayed retention deficits in the probe trials 14 days post-injury. However, after the reminding procedure, injured animals displayed sham-level performance during the second probe trial. The results of these experiments suggest that with anterograde memory impairment induced by traumatic brain injury, the primary deficit lies in task acquisition, not the retention of information within long-term memory. Retrograde memory impairment following injury appears to be mediated primarily by deficits in memory retrieval.

Primary objective: We provide a review of recent chronic and delayed rehabilitative pharmacological treatments examined in experimental models of traumatic brain injury. There is a specific emphasis on studies aiming to enhance cognitive recovery. Main outcomes and results: Decreased neuronal activity is believed to contribute to persistent cognitive disabilities. Neurotransmitter based rehabilitative treatments that increase neuronal activity may assist in the recovery of cognitive function. However, timing and dosage of drug treatment are influential in cognitive enhancement. Drug treatments that affect single and multiple neurotransmitter systems have the ability to significantly influence recovery of function following brain injury. Conclusions: Understanding the relationship between neural disturbances and functional deficits following brain injury is challenging. Cognitive impairment may be the result of a single event or multiple events that occur after the initial insult. Increasing neuronal activity during the chronic phase of injury seems to be an effective treatment strategy for facilitating cognitive recovery. Pharmacological agents do not necessarily display the same effects in an injured brain as in a non-injured brain. Thus, further research is needed to establish the effectiveness of rehabilitative drug treatments.