Prefrontal control of superior colliculus modulates innate escape behavior following adversity.

Innate defensive responses, though primarily instinctive, must also be highly adaptive to changes in risk assessment. However, adaptive changes can become maladaptive, following severe stress, as seen in posttraumatic stress disorder (PTSD). In a series of experiments, we observed long-term changes in innate escape behavior of male mice towards a previously non-threatening stimulus following an adverse shock experience manifested as a shift in the threshold of threat response. By recording neural activity in the superior colliculus (SC) while phototagging specific responses to afferents, we established the crucial influence of input arriving at the SC from the medial prefrontal cortex (mPFC), both directly and indirectly, on escape-related activity after adverse shock experience. Inactivating these specific projections during the shock effectively abolished the observed changes. Conversely, optogenetically activating them during encounters controlled escape responses. This establishes the necessity and sufficiency of those specific mPFC inputs into the SC for adverse experience related changes in innate escape behavior.

The role of hippocampal CaMKII in resilience to trauma-related psychopathology.

Traumatic stress exposure can form persistent trauma-related memories. However, only a minority of individuals develop post-traumatic stress disorder (PTSD) symptoms upon exposure. We employed a rat model of PTSD, which enables differentiating between exposed-affected and exposed-unaffected individuals. Two weeks after the end of exposure, male rats were tested behaviorally, following an exposure to a trauma reminder, identifying them as trauma 'affected' or 'unaffected.' In light of the established role of hippocampal synaptic plasticity in stress and the essential role of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in hippocampal based synaptic plasticity, we pharmacologically inhibited CaMKII or knocked-down (kd) αCaMKII (in two separate experiments) in the dorsal dentate gyrus of the hippocampus (dDG) following exposure to the same trauma paradigm. Both manipulations brought down the prevalence of 'affected' individuals in the trauma-exposed population. A day after the last behavioral test, long-term potentiation (LTP) was examined in the dDG as a measure of synaptic plasticity. Trauma exposure reduced the ability to induce LTP, whereas, contrary to expectation, αCaMKII-kd reversed this effect. Further examination revealed that reducing αCaMKII expression enables the formation of αCaMKII-independent LTP, which may enable increased resilience in the face of a traumatic experience. The current findings further emphasize the pivotal role dDG has in stress resilience.

The Invisibility of Mild Traumatic Brain Injury: Impaired Cognitive Performance as a Silent Symptom.

The present study was designed to tackle two notorious features of mild traumatic brain injury (mTBI)-heterogeneity and invisibility-by characterizing the full scope of mTBI symptoms. Mice were exposed to brain injuries of different intensities utilizing a weight-drop model (10, 30, 50, and 70 g) and subsequently subjected to a comprehensive battery of behavioral tests at different time points and immunohistochemical examination of cortical slices. Whereas the physiological, neurological, emotional, and motor function of mTBI mice (i.e., their well-being) remained largely intact, cognitive deficits were identified by the y-maze and novel object recognition. Results from these two cognitive tests were combined and a dose-response relationship was established between injury intensity and cognitive impairment, ranging from an 85% decline after a 70-g impact (p < 0.001) to a 20% decline after a 10-g impact (essentially no effect). In addition, higher intensities of injury were accompanied by decreased expression of axonal and synaptic markers. Thus, our mTBI mice showed a clear discrepancy between performance (poor cognitive function) and appearance (healthy demeanor). This is of major concern given that diagnosis of mTBI is established on the presence of clinical symptoms and emphasizes the need for an alternative diagnostic modality.

Responses of dural mast cells in concussive and blast models of mild traumatic brain injury in mice: Potential implications for post-traumatic headache.

BACKGROUND: Chronic post-traumatic headache (PTH) is one of the most common symptoms of mild traumatic brain injury (mTBI) but its underlying mechanisms remain unknown. Inflammatory degranulation of dural mast cells (MCs) is thought to promote headache, and may play a role in PTH. Whether mTBI is associated with persistent degranulation of dural MCs is yet to be determined. METHODS: Histochemistry was used to evaluate time course changes in dural MC density and degranulation level in concussive head trauma and blast mouse models of mTBI. The effects of sumatriptan and the MC stabilizer cromolyn sodium on concussion-evoked dural MC degranulation were also investigated. RESULTS: Concussive head injury evoked persistent MC degranulation for at least 30 days. Blast trauma gave rise to a delayed MC degranulation response commencing at seven days that also persisted for at least 30 days. Neither sumatriptan nor cromolyn treatment reduced concussion-evoked persistent MC degranulation. CONCLUSIONS: mTBI evoked by closed head injury or blast exposure is associated with persistent dural MC degranulation. Such a response in mTBI patients may contribute to PTH. Amelioration of PTH by sumatriptan may not involve inhibition of dural MC degranulation. If persistent dural MC degranulation contributes to PTH, then cromolyn treatment may not be effective.

The intriguing effects of ecstasy (MDMA) on cognitive function in mice subjected to a minimal traumatic brain injury (mTBI).

RATIONALE: The use of ecstasy (MDMA) among young adults has dramatically increased over the years. Since MDMA may impair the users' driving ability, the risk of being involved in a motor vehicle accident (MVA) is notably increased. Minimal traumatic brain injury (mTBI) a common consequence of MVAs-produces short- and long-term physical, cognitive, and emotional impairments. OBJECTIVES: To investigate the effects of an acute dose of MDMA in mice subjected to closed head mTBI. METHODS: Mice received 10 mg/kg MDMA 1 h prior to the induction of mTBI. Behavioral tests were conducted 7 and 30 days post-injury. In addition to the behavioral tests, phosphorylation of IGF-1R, ERK, and levels of tyrosine hydroxylase (TH) were measured. RESULTS: mTBI mice showed major cognitive impairments in all cognitive tests conducted. No additional impairments were seen if mTBI was preceded by one dose of MDMA. On the contrary, a beneficial effect was seen in these mice. The western blot analysis of TH revealed a significant decrease in the mTBI mice. These decreases were reversed in mice that were subjected to MDMA prior to the trauma. CONCLUSIONS: The presence of MDMA at the time of mTBI minimizes the alteration of visual and spatial memory of the injured mice. The IGF-1R pathway was activated due to mTBI and MDMA but was not the main contributor to the cognitive improvements. MDMA administration inverted the TH decreases seen after injury. We believe this may be the major cause of the cognitive improvements seen in these mice.

The intricate involvement of the Insulin-like growth factor receptor signaling in mild traumatic brain injury in mice.

Insulin-like growth factor-1 (IGF-1) was suggested as a potential neuroprotective treatment for traumatic brain injury (TBI) induced damage (cognitive as well as cellular). The main goal of the present study was to evaluate the role of the IGF-1R activation in spatial memory outcome following mild traumatic brain injury. mTBI-induced phosphorylation of IGF-1R, AKT and ERK1/2, in mice hippocampus, which was inhibited when mice were pretreated with the selective IGF-1R inhibitor AG1024. IGF-1 administration prevented spatial memory deficits following mTBI. Surprisingly, blocking the IGF-1R signaling in mTBI mice did not augment the spatial memory deficit. In addition, this data imply an intriguing and complex role of the IGF-1 signaling axis in the cellular and behavioral events following mTBI.

Protean behavior under barn-owl attack: voles alternate between freezing and fleeing and spiny mice flee in alternating patterns.

When attacking a spiny mouse in an experimental arena, a barn owl launched a few attacks from distant perches, made repetitive short-distance swoops in each attack and remained in the vicinity of the prey while chasing it. The spiny mouse fled in response, and typically oriented to face the owl whenever it stopped. When attacking a vole, the barn owl performed a greater number of attacks from distant perches, and left the vicinity of the prey after a few short-distance chases or capture attempts. Voles responded to these attacks in unspecific combinations of freezing and fleeing, and did not turn to face the owl when they stopped. Four conclusions are drawn from these encounters. First, two strategies characterized these predator-prey interactions; in one, both predator and prey continuously maintained awareness of each other's location; whereas in the other they continuously attempted to avoid the attention of the other. Second, responses of spiny mice and voles were a manifestation of protean behavior, with spiny mice fleeing in an alternating pattern and voles alternating between running and freezing. Third, locomotor response to owl attack comprised behavior that is an augmentation of normal behavior, with voles clinging to the walls and spiny mice running with frequent and irregular changes in direction. Fourth, the different defensive responses accord with the motor capacities and habitat of each rodent species. All in all, these results demonstrate the dynamic and multidimensional nature of predator-prey interactions.

Rodents in open space adjust their behavioral response to the different risk levels during barn-owl attack.

BACKGROUND: Previous studies have revealed that the response of prey species to predatory risk comprised either freezing (when the prey remained immobile), or fleeing (when it ran frantically in order to remove itself from the vicinity of the predator). Other studies, however, have suggested that the prey will adjust its behavior to risk level. The present study was designed to follow the attacks of a barn owl (Tyto alba) on common spiny mice (Acomys cahirinus) and social voles (Microtus socialis guntherei), in order to reveal the correspondence between the behavior of the owl, the risk level at each phase of the owl's attack, and the defensive behavior of the rodents. RESULTS: Spiny mice dramatically increased the traveled distance upon the appearance of the owl, and kept moving during its attack while taking long trajectories of locomotion. Defensive response in voles dichotomized: in some voles traveled distance dropped when the owl appeared, reaching zero during its attack. In other voles, traveled distance dramatically increased once the owl appeared and further increased under its attack. These defensive responses developed by gradual tuning of normal locomotor behavior in accordance with the level of risk. CONCLUSIONS: The phenotypic difference in defensive behavior between voles and spiny mice probably stems from their different habitats and motor capacities. Agility and running capacity, together with a relatively sheltered natural habitat, make fleeing the most appropriate response for spiny mice during owl attack. Clumsiness and relatively limited motor capacities, together with an open natural habitat, account for the dichotomy to freezing or fleeing in voles. Thus, the apparent species-specific anti-predator response in spiny mice and voles is based on species-specific normal locomotor behavior, which depends on the species-specific ecology and motor capacity, and behaviors like defensive attack or escape jump that are specific to life threat. The latter behaviors are brief, and irregularly inlaid in the ongoing locomotor behavior. Finally, our results show that in both voles and spiny mice there is a gradual transition from normal to defensive behavior in accordance with the increase in risk level.