Basolateral amygdala stimulation plus water maze training restore dentate gyrus LTP and improve spatial learning and memory.

Synaptic plasticity is a key mechanism of neural plasticity involved in learning and memory. A reduced or impaired synaptic plasticity could lead to a deficient learning and memory. On the other hand, besides reducing hipocampal dependent learning and memory, fimbria-fornix lesion affects LTP. However, we have consistently shown that stimulation of the basolateral amygdala (BLA) 15 min after water maze training is able to improve spatial learning and memory in fimbria fornix lesioned rats while also inducing changes in the expression of plasticity-related genes expression in memory associated brain regions like the hippocampus and prefrontal cortex. In this study we test that hypothesis: whether BLA stimulation 15 min after water maze training can improve LTP in the hippocampus of fimbria-fornix lesioned rats. To address this question, we trained fimbria-fornix lesioned rats in water maze for four consecutive days, and the BLA was bilaterally stimulated 15 min after each training session.Our data show that trained fimbria-fornix lesioned rats develop a partially improved LTP in dentated gyrus compared with the non-trained fimbria-fornix lesioned rats. In contrast, dentated gyrus LTP in trained and BLA stimulated fimbria-fornix lesioned rats improved significantly compared to the trained fimbria-fornix lesioned rats, but was not different from that shown by healthy animals. BLA stimulation in non-trained FF lesioned rats did not improve LTP; instead produces a transient synaptic depression. Restoration of the ability to develop LTP by the combination of training and BLA stimulation would be one of the mechanisms involved in ameliorating memory deficits in lesioned animals.

Title: Injury characteristics of the Papez circuit in patients with diffuse axonal injury: a diffusion tensor tractography study.

We investigate the characteristics of injury of four portions of the Papez circuit in patients with diffuse axonal injury (DAI), using diffusion tensor tractography (DTT). Thirty-four consecutive patients with DAI and 30 normal control subjects were recruited. Four portions of the Papez circuit were reconstructed: the fornix, cingulum, thalamocingulate tract, and mammillothalamic tract. Analysis of DTT parameters [fractional anisotropy (FA) and tract volume (TV)] and configuration (narrowing, discontinuation, or non-reconstruction) was performed for each portion of the Papez circuit. The Memory Assessment Scale (MAS) was used for the estimation of cognitive function. In the group analysis, decreased fractional anisotropy and tract volume of the entire Papez circuit were observed in the patient group compared with the control group (p < 0.05). In the individual analysis, all four portions of the Papez circuit were injured in terms of DTT parameters or configuration. Positive correlation was observed between TV of the fornix and short-term memory on MAS r = 0.618, p < 0.05), and between FA of the fornix and total memory on MAS (r = 0.613, p < 0.05). We found that all four portions of the Papez circuit in the patient group were vulnerable to DAI, and among four portions of the Papez circuit, the fornix was the most vulnerable portion in terms of injury incidence and severity.

Relation Between Memory Impairment and the Fornix Injury in Patients With Mild Traumatic Brain Injury: A Diffusion Tensor Tractography Study.

OBJECTIVE: We investigated the relation between memory impairment and the fornix injury in patients with mild traumatic brain injury, using diffusion tensor tractography. DESIGN: Eighty-six chronic patients with mild traumatic brain injury and 50 normal control subjects were recruited. Fractional anisotropy and fiber volume were measured for each reconstructed fornix. The patients were classified according to the following three types: type A (47 patients), intact integrity of both fornical crura; type B (27 patients), showed a discontinuation in either fornical crus; and type C (12 patients), discontinuations in both fornical crura. The Memory Assessment Scale was used for evaluation of memory function. RESULTS: Fractional anisotropy and fiber volume showed weak positive correlations with global memory of Memory Assessment Scale, respectively (r = 0.303, P = 0.006; r = 0.271, P = 0.014). Significant difference in the global memory of Memory Assessment Scale was observed between type A and B and between type A and C without difference between type B and C (P < 0.05). CONCLUSION: It seems that the diffusion tensor tractography parameters of the fornix and the integrity of fornical crus can be used as a biomarker for axonal injury of the fornix in patients with mild traumatic brain injury.

Erythropoietin improves object placement recognition memory in a time dependent manner in both, uninjured animals and fimbria-fornix-lesioned male rats.

An increasing number of reports sustain a possible role of erythropoietin (EPO) as neuroprotective agent. In two previous articles we have evaluated EPO as plasticity promoting agent, and to contribute the restoration of brain function affected by acquired damage. We have shown that EPO is able to induce an increased synaptic efficacy in vivo along with a plasticity promoting effect. In the Morris water maze EPO administration to fimbria-fornix lesioned male rats induces a significant improvement of their spatial memory, affected by the lesion. Singularly, EPO was only effective when administered shortly after training (10 min) but not after several hours (5 h), suggesting a specific EPO effect on time dependent plasticity process. In the present paper we have expanded this line of evidence using a low stress paradigm of object placement recognition in lesioned and healthy male rats. The memory trace in this model is short-lasting; animals could recognize the change in object position when tested 24 h after, but not 48 or 72 h after the acquisition session. EPO administration 10 min after acquisition significantly prolongs retention to, at least, 72 h in healthy rats. No effect was seen if EPO was administered 5 h after training, suggesting a specific EPO modulatory effect on the consolidation process. Remarkably, early EPO treatment to fimbria fornix lesioned animals reverts the memory deficit caused by the lesion. An increased expression of the plasticity related gene arc, was also confirmed in the hippocampus and the prefrontal cortex, that is likely to be involved in the behavioral improvement observed.

Injury of the Precommissural Fornix in a Patient with Subarachnoid Hemorrhage: A Case Report.

OBJECTIVES: We investigated injury of the pre- or postcommissural fornix in a patient with subarachnoid hemorrhage (SAH) using diffusion tensor imaging. CASE DESCRIPTION: A 48-year-old male patient was diagnosed as SAH due to rupture of the right middle cerebral artery bifurcation aneurysm. After 9 weeks from onset, he was transferred to the rehabilitation department and he showed memory impairment. The whole fornix was reconstructed using single-tract fornix model based on a fiber assignment by continuous tracking, and separated fornices (pre- and postcommissural fornices) were reconstructed using 2-tract fornix model based on a probabilistic tractography method. The fractional anisotropy (FA), mean diffusivity, and fiber volume were measured in the patient and 6 normal control subjects. The integrities of both reconstructed whole fornices that were reconstructed using probabilistic tractography method were preserved. By contrast, in the results of 2-tract fornix model, the precommissural fornices showed discontinuations in both fornical cruses. In addition, the FA and fiber volume of both precommissural fornices in the patient were decreased by more than 2 standard deviations of those of normal control subjects. CONCLUSIONS: Separate evaluations of the pre- and postcommissural fornices using 2-tract fornix model would be useful for diagnosis in patients with memory impairment following SAH.

Results of Combined Intraventricular Neuroendoscopic Procedures in 130 Cases with Special Focus on Fornix Contusions.

OBJECTIVE: Increasing experience with intraventricular neuroendoscopic procedures shows good results in the combination of endoscopic third ventriculostomy (ETV) and tumor biopsy. Other possible combinations are mainly presented in subgroups in the literature. Here, we present our experience with combined intraventricular procedures within 1 setting over the last 2 decades. METHODS: This study retrospectively analyzes data from neuroendoscopic intraventricular procedures between 1993 and 2015 in 3 different departments of neurosurgery. Inclusion criteria were a combination of at least 2 intraventricular endoscopic procedures (e.g. third ventriculostomy, cyst fenestration, tumor surgery or aqueductoplasty) within 1 setting. RESULTS: One-hundred and thirty cases with more than 300 procedures fulfilled the inclusion criteria. The most frequent combinations were ETV and tumor biopsy (n = 36), ETV and aqueductoplasty/stenting (n = 30), and ETV and cyst fenestration (n = 18). The complication rate was 16.9% with an overall morbidity of 1.6% and mortality of 0.8%. Fornix contusion was one of the most frequent intraoperative complications (16.4%). Shunt independency was achieved in 82.9% of cases with hydrocephalic symptoms. CONCLUSIONS: A combination of different intraventricular endoscopic procedures is safe and reliable, bearing similar risks of morbidities and mortality to single neuroendoscopic procedures. This study is one of the largest series in the literature and has similar low complication rates to others. Fornix contusion is the most frequent intraoperative complication in these patients. However, obvious clinical correlation is rare.

Differences in Callosal and Forniceal Diffusion between Patients with and without Postconcussive Migraine.

BACKGROUND AND PURPOSE: Posttraumatic migraines are common after mild traumatic brain injury. The purpose of this study was to determine if a specific axonal injury pattern underlies posttraumatic migraines after mild traumatic brain injury utilizing Tract-Based Spatial Statistics analysis of diffusion tensor imaging. MATERIALS AND METHODS: DTI was performed in 58 patients with mild traumatic brain injury with posttraumatic migraines. Controls consisted of 17 patients with mild traumatic brain injury without posttraumatic migraines. Fractional anisotropy and diffusivity maps were generated to measure white matter integrity and were evaluated by using Tract-Based Spatial Statistics regression analysis with a general linear model. DTI findings were correlated with symptom severity, neurocognitive test scores, and time to recovery with the Pearson correlation coefficient. RESULTS: Patients with mild traumatic brain injury with posttraumatic migraines were not significantly different from controls in terms of age, sex, type of injury, or neurocognitive test performance. Patients with posttraumatic migraines had higher initial symptom severity (P = .01) than controls. Compared with controls, patients with mild traumatic brain injury with posttraumatic migraines had decreased fractional anisotropy in the corpus callosum (P = .03) and fornix/septohippocampal circuit (P = .045). Injury to the fornix/septohippocampal circuit correlated with decreased visual memory (r = 0.325, P = .01). Injury to corpus callosum trended toward inverse correlation with recovery (r = -0.260, P = .05). CONCLUSIONS: Injuries to the corpus callosum and fornix/septohippocampal circuit were seen in patients with mild traumatic brain injury with posttraumatic migraines, with injuries in the fornix/septohippocampal circuit correlating with decreased performance on neurocognitive testing.

Delayed degeneration of the left fornical crus with verbal memory impairment in a patient with mild traumatic brain injury: A case report.

RATIONALE: We report on a patient who showed delayed degeneration of the left fornical crus with verbal memory impairment following mild traumatic brain injury (TBI), which was demonstrated by diffusion tensor tractography (DTT). PATIENT CONCERNS:: fter flexion and hyperextension of her head to the opposite side, the patient experienced a dazed feeling for a while at the time of head trauma. The patient's Glasgow Coma Scale score was 15, and mini-mental state examination score was 30. DIAGNOSES: A 50-year-old right-handed female with 12 years of education suffered from head trauma resulting from a car accident. INTERVENTIONS: A The patient showed normal memory function at one year after onset: the Memory Assessment Scale (global memory: 124 (95 percentile (%ile)), verbal memory: 111 (77%ile), and visual memory: 132 (98%ile) (A percentile is a measure used in statistics indicating the value below which a given percentage of observations in a group of observations fall). However, the patient began to experience decline of memory function such as forgetfulness at approximately 1.5 years after onset. On the 2-year evaluation, she showed decrement of memory function (global memory: 108 (70%ile), verbal memory: 86 (18%ile), and visual memory: 129 (97%ile). OUTCOMES: On 1-year DTT, the integrity of the fornix was well preserved between the fornical column and fornical crus. However, on 2-year DTT, a discontinuation was observed in the left fornical crus. LESSONS: Delayed degeneration of the left fornical crus was demonstrated in a patient who showed delayed onset of verbal memory impairment following mild TBI.

Effects of different delayed exercise regimens on cognitive performance in fimbria­fornix transected rats.

Studies have shown that exercise can positively influence cognitive performance after brain injury. This study investigated the effects of different exercise regimens on allocentric place learning after fimbria­fornix (FF) transection. One hundred and sixteen pre­shaped rats were subjected either to a mechanical transection of the FF or control sham surgery and divided into following groups: i) no exercise (NE), ii) voluntary exercise in a running wheel (RW), iii) forced swimming exercise administered as interval training of short (3x5 min) duration (FS­SI), iv) forced swimming exercise administered as interval training of long (3x15 min) duration (FS­LI), v) forced swimming exercise administered as one session of short (5 min) duration (FS­SS), and vi) forced swimming exercise administered as one session of long (15 min) duration (FS­LS). The exercise was initiated 21 days post­surgery. Subsequently, all animals were administered 28 acquisition sessions in an 8­arm radial maze. Both sham operated and lesioned animals showed a significant learning response, however, the lesion induced a marked and lasting impairment, which was not alleviated neither by voluntary nor forced (spaced or one­session only) exercise regimens. Exercise regimens had no effect on the place learning of control sham animals. We conclude that the lesion location as well as factors related to the exercise­ and cognitive testing protocols can profoundly influence the potential of exercise as a general recovery­promoting method.

Amygdala electrical stimulation inducing spatial memory recovery produces an increase of hippocampal bdnf and arc gene expression.

Amygdala seems to promote the consolidation of plastic modification in different brain areas and these long-term brain changes require a rapid de novo RNA and protein synthesis. We have previously shown that basolateral amygdala electrical stimulation produces a partial recovery of spatial memory in fimbria-fornix lesioned animals and it is also able to increase the BDNF protein content in the hippocampus. The emerging question is whether these increased BDNF protein content arises from previously synthesized RNA or from de novo RNA expression. Now we address the question if amygdala electrical stimulation 15min after daily water maze training produces a rapid de novo RNA synthesis in the hippocampus, a critical brain area for spatial memory recovery in fimbria-fornix lesioned animals. In addition, we also study RNA arc expression, a gene which is essential for memory and neural plasticity processes. To this purpose, we study amygdala stimulation effects on the expression of plasticity related-early-genes bdnf and arc in the hippocampus of fimbria-fornix lesioned animals trained in a water-maze for 4days. We also checked on the expression of both genes in non-lesioned, untrained animals (acute condition) at 0.5, 1, 2 and 24h after basolateral amygdala electrical stimulation. Our data from trained animals confirm that daily amygdala electrical stimulation 15min after water maze training produces a partial memory recovery and that is coupled to an increase of bdnf and arc genes expression in the hippocampus. Additionally, the acute study shows that a single session of amygdala stimulation induces a transient increase of both genes (peaking at 30min). These results confirm the memory improving effect of amygdala stimulation in fimbria-fornix-lesioned animals and sustain the assumption that the memory improving effect is mediated by newly synthetized BDNF acting on a memory relevant structure like the hippocampus. The increased amount of BDNF within the hippocampus seems to be locally synthetized by mechanisms activated by the amygdala stimulation.

Exercise-induced improvement in cognitive performance after fimbria-fornix transection depends on the timing of exercise administration.

BACKGROUND: Exercise after brain injury holds major therapeutic potentials, but it is still uncertain whether such an intervention should take place during the critical time window of intrinsic repair mechanisms. OBJECTIVE: To assess the effects of acute or delayed voluntary exercise in running wheels on post-injury allocentric place learning in an 8-arm radial maze. METHODS: Forty-eight pre-shaped male rats underwent fimbria-fornix transection (FF) or control surgery (Sham). The animals were divided into six groups: FF group with no access to exercise (FF/NE); FF group starting exercise 1day post-surgery (FF/E+1); FF group starting exercise 8days post-surgery (FF/E+8); FF group starting exercise 21days post-surgery (FF/E+21); Sham group with no access to exercise (Sham/NE), and Sham group starting exercise 1day post-surgery (Sham/E+1). After 7days of exercise 6h/day, all animals underwent 28 place learning acquisition sessions. RESULTS: The FF/E+21 group showed an enhanced acquisition of the task compared to FF/NE. The FF/E+1 and FF/E+8 groups also showed an enhanced task acquisition relative to FF/NE, however with a slower acquisition than the FF/E+21 group. CONCLUSION: The data underscores the link between exercise and functional recovery after brain injury and emphasizes the importance of optimal timing of this intervention.

Implementation of a Functional Observation Battery for the Assessment of Postoperative Well-being in Rats Subjected to Fimbria-Fornix Transection.

The postoperative well-being of Wistar rats subjected to fimbria-fornix transections was assessed using a functional observational battery (FOB), including observations of relative body weight change, general condition, fur quality, body posture and movement, appetite, and pica behavior. Fimbria-fornix transected animals (FF), sham-operated animals (Sham), and two non-operated control groups with and without administration of buprenorphine (+BUP and -BUP, respectively) were observed twice daily for seven days after surgery. Buprenorphine (0.4 mg/kg) mixed in a nut paste for voluntary ingestion was supplied twice daily for 84 h to all groups except the -BUP control group starting on the day of surgery. Body weight was slightly decreased postoperatively in both surgical groups (FF and Sham) compared to control groups. The +BUP control group lost weight starting at day four after discontinuation of buprenorphine. Furthermore, the FF group exhibited significantly reduced general condition one day after surgery, with significantly affected body posture and movement for two days after surgery. In addition, mild pica behavior was observed in the FF group during the first postsurgical day. In conclusion, the FOB implemented in the present study appears to be a sensitive and accurate protocol for assessing animal well-being in the experimental setup applied. It is apparent that the FF transection is an invasive procedure that causes mildly adverse postoperative effects on the rats' well-being. We therefore recommend that this FOB is applied as a routine welfare monitoring protocol in experiments using mechanical central nervous system injury models, such as FF transection.

Adaptability to changes in temporal structure is fornix-dependent.

Recognition memory deficits, even after short delays, are sometimes observed following hippocampal damage. One hypothesis links the hippocampus with processes in updating contextual memory representation. Here, we used fornix transection, which partially disconnects the hippocampal system, and compares the performance of fornix-transected monkeys with normal monkeys on two versions of a delayed-matching-to-position task with short delays. Spatial recognition memory was affected by fornix transection only when the temporal structure of the task changed across trials, while differences in motor control, motivation, perception, or short-term memory were not critical. We attributed the deficit to a compromised ability in tracking changes in task temporal structure.

Erythropoietin Promotes Neural Plasticity and Spatial Memory Recovery in Fimbria-Fornix-Lesioned Rats.

BACKGROUND: Erythropoietin (EPO) upregulates the mitogen activated protein kinase (MAPK) cascade, a central signaling pathway in cellular plastic mechanisms, and is critical for normal brain development. OBJECTIVE: We hypothesized that EPO could modulate the plasticity mechanisms supporting spatial memory recovery in fimbria-fornix-transected animals. METHODS: Fimbria-fornix was transected in 3 groups of rats. Seven days later, EPO was injected daily for 4 consecutive days within 10 minutes after training on a water maze task. RESULTS: Our results show that EPO injections 10 minutes after training produced a substantial spatial memory recovery in fimbria-fornix-lesioned animals. In contrast, an EPO injection shortly after fimbria-fornix lesion surgery does not promote spatial-memory recovery. Neither does daily EPO injection 5 hours after the water maze performance. EPO, on the other hand, induced the expression of plasticity-related genes like arc and bdnf, but this effect was independent of training or lesion. CONCLUSIONS: This finding supports our working hypothesis that EPO can modulate transient neuroplastic mechanisms triggered by training in lesioned animals. Consequently, we propose that EPO administration can be a useful trophic factor to promote neural restoration when given in combination with training.

Fornical and nonfornical projections from the rat hippocampal formation to the anterior thalamic nuclei.

The hippocampal formation and anterior thalamic nuclei form part of an interconnected network thought to support memory. A central pathway in this mnemonic network comprises the direct projections from the hippocampal formation to the anterior thalamic nuclei, projections that, in the primate brain, originate in the subicular cortices to reach the anterior thalamic nuclei by way of the fornix. In the rat brain, additional pathways involving the internal capsule have been described, linking the dorsal subiculum to the anteromedial thalamic nucleus, as well as the postsubiculum to the anterodorsal thalamic nucleus. Confirming such pathways is essential in order to appreciate how information is transferred from the hippocampal formation to the anterior thalamus and how it may be disrupted by fornix pathology. Accordingly, in the present study, pathway tracers were injected into the anterior thalamic nuclei and the dorsal subiculum of rats with fornix lesions. Contrary to previous descriptions, projections from the subiculum to the anteromedial thalamic nucleus overwhelmingly relied on the fornix. Dorsal subiculum projections to the majority of the anteroventral nucleus also predominantly relied on the fornix, although postsubicular inputs to the lateral dorsal part of the anteroventral nucleus, as well as to the anterodorsal and laterodorsal thalamic nuclei, largely involved a nonfornical pathway, via the internal capsule.

Stromal derived factor-1α in hippocampus radial glial cells in vitro regulates the migration of neural progenitor cells.

Stromal derived factor-1α (SDF-1α), a critical chemokine that promotes cell homing to target tissues, was presumed to be involved in the traumatic brain injury cortex. In this study, we determined the expression of SDF-1α in the hippocampus after transection of the fimbria fornix (FF). Realtime PCR and ELISA showed that mRNA transcription and SDF-1α proteins increased significantly after FF transection. In vitro, the expression of SDF-1α in radial glial cells (RGCs) incubated with deafferented hippocampus extracts was observed to be greater than in those incubated with normal hippocampus extracts. The co-culture of neural progenitor cells (NPCs) and RGCs indicated that the extracts of deafferented hippocampus induced more NPCs migrating toward RGCs than the normal extracts. Suppression or overexpression of SDF-1α in RGCs markedly either decreased or increased, respectively, the migration of NPCs. These results suggest that after FF transection, SDF-1α in the deafferented hippocampus was upregulated and might play an important role in RGC induction of NPC migration; therefore, SDF-1α is a target for additional research for determining new therapy for brain injuries.

The impact of fornix lesions in rats on spatial learning tasks sensitive to anterior thalamic and hippocampal damage.

The present study sought to understand how the hippocampus and anterior thalamic nuclei are conjointly required for spatial learning by examining the impact of cutting a major tract (the fornix) that interconnects these two sites. The initial experiments examined the consequences of fornix lesions in rats on spatial biconditional discrimination learning. The rationale arose from previous findings showing that fornix lesions spare the learning of spatial biconditional tasks, despite the same task being highly sensitive to both hippocampal and anterior thalamic nuclei lesions. In the present study, fornix lesions only delayed acquisition of the spatial biconditional task, pointing to additional contributions from non-fornical routes linking the hippocampus with the anterior thalamic nuclei. The same fornix lesions spared the learning of an analogous nonspatial biconditional task that used local contextual cues. Subsequent tests, including T-maze place alternation, place learning in a cross-maze, and a go/no-go place discrimination, highlighted the impact of fornix lesions when distal spatial information is used flexibly to guide behaviour. The final experiment examined the ability to learn incidentally the spatial features of a square water-maze that had differently patterned walls. Fornix lesions disrupted performance but did not stop the rats from distinguishing the various corners of the maze. Overall, the results indicate that interconnections between the hippocampus and anterior thalamus, via the fornix, help to resolve problems with flexible spatial and temporal cues, but the results also signal the importance of additional, non-fornical contributions to hippocampal-anterior thalamic spatial processing, particularly for problems with more stable spatial solutions.

Changes of an injured fornix in a patient with mild traumatic brain injury: diffusion tensor tractography follow-up study.

BACKGROUND: This study investigated the changes of an injured fornix from early stage to chronic stage in a patient with mild traumatic brain injury (TBI), using diffusion tensor tractography (DTT). METHODS: A 25-year-old female suffered from head trauma resulting from a pedestrian car accident. The patient showed a total score of 86 for memory impairment on the Memory Assessment Scale at 2 weeks after onset; however, her memory has been recovered to within normal range, with a score of 105 at 9 months after onset. RESULTS: The middle portion of the right fornical crus showed narrowing and the discontinued left fornical crus was shortened on 9-month DTT compared with 2-week DTT. Two branches from the right fornical column and body were observed on 9-month DTT; in contrast, the two branches from the left fornical column and the left fornical body were elongated and shortened, respectively, on 9-month DTT compared with 2-week DTT. CONCLUSIONS: The narrowed lesion in the middle of the right fornical crus and the shortening of the discontinued left fornical crus appear to indicate degeneration following traumatic axonal injury. In contrast, the neural branches from both fornices appear to be related to the functional recovery mechanisms of the injured fornix.