Development of an MR-Guided Focused Ultrasound (MRgFUS) Lesioning Approach for the Fornix in the Rat Brain.

OBJECTIVE: High-intensity magnetic resonance-guided focused ultrasound (MRgFUS) is a non-invasive therapy to lesion brain tissue, used clinically in patients and pre-clinically in several animal models. Challenges with focused ablation in rodent brains can include skull and near-field heating and accurately targeting small and deep brain structures. We overcame these challenges by creating a novel method consisting of a craniectomy skull preparation, a high-frequency transducer (3 MHz) with a small ultrasound focal spot, a transducer positioning system with an added manual adjustment of ∼0.1 mm targeting accuracy, and MR acoustic radiation force imaging for confirmation of focal spot placement. METHODS: The study consisted of two main parts. First, two skull preparation approaches were compared. A skull thinning approach (n = 7 lesions) was compared to a craniectomy approach (n = 22 lesions), which confirmed a craniectomy was necessary to decrease skull and near-field heating. Second, the two transducer positioning systems were compared with the fornix chosen as a subcortical ablation target. We evaluated the accuracy of targeting using histologic methods from a high-frequency transducer with a small ultrasound focal spot and MR acoustic radiation force imaging. RESULTS: Comparing a motorized adjustment system (∼1 mm precision, n = 17 lesions) to the motorized system with an added micromanipulator (∼0.1 mm precision, n = 14 lesions), we saw an increase in the accuracy of targeting the fornix by 133%. CONCLUSIONS: The described work allows for repeatable and accurate targeting of small and deep structures in the rodent brain, such as the fornix, enabling the investigation of neurological disorders in chronic disease models.

Disruption of awake sharp-wave ripples does not affect memorization of locations in repeated-acquisition spatial memory tasks.

Storing and accessing memories is required to successfully perform day-to-day tasks, for example for engaging in a meaningful conversation. Previous studies in both rodents and primates have correlated hippocampal cellular activity with behavioral expression of memory. A key role has been attributed to awake hippocampal replay - a sequential reactivation of neurons representing a trajectory through space. However, it is unclear if awake replay impacts immediate future behavior, gradually creates and stabilizes long-term memories over a long period of time (hours and longer), or enables the temporary memorization of relevant events at an intermediate time scale (seconds to minutes). In this study, we aimed to address the uncertainty around the timeframe of impact of awake replay by collecting causal evidence from behaving rats. We detected and disrupted sharp wave ripples (SWRs) - signatures of putative replay events - using electrical stimulation of the ventral hippocampal commissure in rats that were trained on three different spatial memory tasks. In each task, rats were required to memorize a new set of locations in each trial or each daily session. Interestingly, the rats performed equally well with or without SWR disruptions. These data suggest that awake SWRs - and potentially replay - does not affect the immediate behavior nor the temporary memorization of relevant events at a short timescale that are required to successfully perform the spatial tasks. Based on these results, we hypothesize that the impact of awake replay on memory and behavior is long-term and cumulative over time.

Sleep Differentially and Profoundly Impairs Recall Memory in a Patient with Fornix Damage.

In March 2020, C.T., a kind, bright, and friendly young woman underwent surgery for a midline tumor involving her septum pellucidum and extending down into her fornices bilaterally. Following tumor diagnosis and surgery, C.T. experienced significant memory deficits: C.T.'s family reported that she could remember things throughout the day, but when she woke up in the morning or following a nap, she would expect to be in the hospital, forgetting all the information that she had learned before sleep. The current study aimed to empirically validate C.T.'s pattern of memory loss and explore its neurological underpinnings. On two successive days, C.T. and age-matched controls watched an episode of a TV show and took a nap or stayed awake before completing a memory test. Although C.T. performed numerically worse than controls in both conditions, sleep profoundly exacerbated her memory impairment, such that she could not recall any details following a nap. This effect was replicated in a second testing session. High-resolution MRI scans showed evidence of the trans-callosal surgical approach's impact on the mid-anterior corpus callosum, indicated that C.T. had perturbed white matter particularly in the right fornix column, and demonstrated that C.T.'s hippocampal volumes did not differ from controls. These findings suggest that the fornix is important for processing episodic memories during sleep. As a key output pathway of the hippocampus, the fornix may ensure that specific memories are replayed during sleep, maintain the balance of sleep stages, or allow for the retrieval of memories following sleep.

Structural Connectivity Changes After Fornix Transection in Macaques Using Probabilistic Diffusion Tractography.

The fornix, the limbic system's white matter tract connecting the extended hippocampal system to subcortical structures of the medial diencephalon, is strongly associated with learning and memory in humans and nonhuman primates (NHPs). Here, we sought to investigate alterations in structural connectivity across key cortical and subcortical regions after fornix transection in NHPs. We collected diffusion-weighted MRI (dMRI) data from three macaque monkeys that underwent bilateral fornix transection during neurosurgery and from four age- and cohort-matched control macaques that underwent surgery to implant a head-post but remained neurologically intact. dMRI data were collected from both groups at two time points, before and after the surgeries, and scans took place at around the same time for the two groups. We used probabilistic tractography and employed the number of tracking streamlines to quantify connectivity across our regions of interest (ROIs), in all dMRI sessions. In the neurologically intact monkeys, we observed high connectivity across certain ROIs, including the CA3 hippocampal subfield with the retrosplenial cortex (RSC), the anterior thalamus with the RSC, and the RSC with the anterior cingulate cortex (ACC). However, we found that, compared to the control group, the fornix-transected monkeys showed marked, significant, connectivity changes including increases between the anterior thalamus and the ACC and between the CA3 and the ACC, as well as decreases between the CA3 and the RSC. Our results highlight cortical and subcortical network changes after fornix transection and identify candidate indirect connectivity routes that may support memory functions after damage and/or neurodegeneration.

Overweight/Obesity-related microstructural alterations of the fimbria-fornix in the ABCD study: The role of aerobic physical activity.

Childhood overweight/obesity has been associated with negative consequences related to brain function and may involve alterations in white matter pathways important for cognitive and emotional processing. Aerobic physical activity is a promising lifestyle factor that could restore white matter alterations. However, little is known about either regional white matter alterations in children with overweight/obesity or the effects of aerobic physical activity targeting the obesity-related brain alterations in children. Using a large-scale cross-sectional population-based dataset of US children aged 9 to 10 years (n = 8019), this study explored the associations between overweight/obesity and microstructure of limbic white matter tracts, and examined whether aerobic physical activity may reduce the overweight/obesity-related white matter alterations in children. The primary outcome measure was restriction spectrum imaging (RSI)-derived white matter microstructural integrity measures. The number of days in a week that children engaged in aerobic physical activity for at least 60 minutes per day was assessed. We found that females with overweight/obesity had lower measures of integrity of the fimbria-fornix, a major limbic-hippocampal white matter tract, than their lean peers, while this difference was not significant in males. We also found a positive relationship between the number of days of aerobic physical activity completed in a week and integrity measures of the fimbria-fornix in females with overweight/obesity. Our results provide cross-sectional evidence of sex-specific microstructural alteration in the fimbria-fornix in children with overweight/obesity and suggest that aerobic physical activity may play a role in reducing this alteration. Future work should examine the causal direction of the relationship between childhood overweight/obesity and brain alterations and evaluate potential interventions to validate the effects of aerobic physical activity on this relationship.

Alcohol-induced damage to the fimbria/fornix reduces hippocampal-prefrontal cortex connection during early abstinence.

INTRODUCTION: Alcohol dependence is characterized by a gradual reduction in cognitive control and inflexibility to contingency changes. The neuroadaptations underlying this aberrant behavior are poorly understood. Using an animal model of alcohol use disorders (AUD) and complementing diffusion-weighted (dw)-MRI with quantitative immunohistochemistry and electrophysiological recordings, we provide causal evidence that chronic intermittent alcohol exposure affects the microstructural integrity of the fimbria/fornix, decreasing myelin basic protein content, and reducing the effective communication from the hippocampus (HC) to the prefrontal cortex (PFC). Using a simple quantitative neural network model, we show how disturbed HC-PFC communication may impede the extinction of maladaptive memories, decreasing flexibility. Finally, combining dw-MRI and psychometric data in AUD patients, we discovered an association between the magnitude of microstructural alteration in the fimbria/fornix and the reduction in cognitive flexibility. Overall, these findings highlight the vulnerability of the fimbria/fornix microstructure in AUD and its potential contribution to alcohol pathophysiology. Fimbria vulnerability to alcohol underlies hippocampal-prefrontal cortex dysfunction and correlates with cognitive impairment.

Deep brain stimulation of fornix in Alzheimer's disease: From basic research to clinical practice.

Alzheimer's disease (AD) is one of the most common progressive neurodegenerative diseases associated with the degradation of memory and cognitive ability. Current pharmacotherapies show little therapeutic effect in AD treatment and still cannot prevent the pathological progression of AD. Deep brain stimulation (DBS) has shown to enhance memory in morbid obese, epilepsy and traumatic brain injury patients, and cognition in Parkinson's disease (PD) patients deteriorates during DBS off. Some relevant animal studies and clinical trials have been carried out to discuss the DBS treatment for AD. Reviewing the fornix trials, no unified conclusion has been reached about the clinical benefits of DBS in AD, and the dementia ratings scale has not been effectively improved in the long term. However, some patients have presented promising results, such as improved glucose metabolism, increased connectivity in cognition-related brain regions and even elevated cognitive function rating scale scores. The fornix plays an important regulatory role in memory, attention, and emotion through its complex fibre projection to cognition-related structures, making it a promising target for DBS for AD treatment. Moreover, the current stereotaxic technique and various evaluation methods have provided references for the operator to select accurate stimulation points. Related adverse events and relatively higher costs in DBS have been emphasized. In this article, we summarize and update the research progression on fornix DBS in AD and seek to provide a reliable reference for subsequent experimental studies on DBS treatment of AD.

A role for the fornix in temporal sequence memory.

Converging evidence from studies of human and nonhuman animals suggests that the hippocampus contributes to sequence learning by using temporal context to bind sequentially occurring items. The fornix is a white matter pathway containing the major input and output pathways of the hippocampus, including projections from medial septum and to diencephalon, striatum, lateral septum and prefrontal cortex. If the fornix meaningfully contributes to hippocampal function, then individual differences in fornix microstructure might predict sequence memory. Here, we tested this prediction by performing tractography in 51 healthy adults who had undertaken a sequence memory task. Microstructure properties of the fornix were compared with those of tracts connecting medial temporal lobe regions but not predominantly the hippocampus: the Parahippocampal Cingulum bundle (PHC) (conveying retrosplenial projections to parahippocampal cortex) and the Inferior Longitudinal Fasciculus (ILF) (conveying occipital projections to perirhinal cortex). Using principal components analysis, we combined Free-Water Elimination Diffusion Tensor Imaging and Neurite Orientation Dispersion and Density Imaging measures obtained from multi-shell diffusion MRI into two informative indices: the first (PC1) capturing axonal packing/myelin and the second (PC2) capturing microstructural complexity. We found a significant correlation between fornix PC2 and implicit reaction-time indices of sequence memory, indicating that greater fornix microstructural complexity is associated with better sequence memory. No such relationship was found with measures from the PHC and ILF. This study highlights the importance of the fornix in aiding memory for objects within a temporal context, potentially reflecting a role in mediating inter-regional communication within an extended hippocampal system.

Prenatal Cafeteria Diet Primes Anxiety-like Behavior Associated to Defects in Volume and Diffusion in the Fimbria-fornix of Mice Offspring.

Prenatal exposure to high-energy diets primes brain alterations that increase the risk of developing behavioral and cognitive failures. Alterations in the structure and connectivity of brain involved in learning and memory performance are found in adult obese murine models and in humans. However, the role of prenatal exposure to high-energy diets in the modulation of the brain's structure and function during cognitive decline remains unknown. We used female C57BL6 mice (n = 10) exposed to a high-energy diets (Cafeteria diet (CAF)) or Chow diet for 9 weeks (before, during and after pregnancy) to characterize their effect on brain structural organization and learning and memory performance in the offspring at two-month-old (n = 17). Memory and learning performance were evaluated using the Y-maze test including forced and spontaneous alternation, novel object recognition (NORT), open field and Barnes maze tests. We found no alterations in the short- or long-time spatial memory performance in male offspring prenatally exposed to CAF diet when compared to the control, but they increased time spent in the edges resembling anxiety-like behavior. By using deformation-based morphometry and diffusion tensor imaging analysis we found that male offspring exposed to CAF diet showed increased volume in primary somatosensory cortex and a reduced volume of fimbria-fornix, which correlate with alterations in its white matter integrity. Biological modeling revealed that prenatal exposure to CAF diet predicts low volume in the fimbria-fornix, which was associated with anxiety in the offspring. The findings suggest that prenatal exposure to high-energy diets prime brain structural alterations related to anxiety in the offspring.

A unique erythropoietin dosage induces the recovery of long-term synaptic potentiation in fimbria-fornix lesioned rats.

Synapses can experience long-term enhancements in its efficacy transmission in an activity-dependent manner (LTP, Long-Term Potentiation). This could contribute to store the living experiences in memory. Consequently, loss of synaptic plasticity can lead to failures in memory encoding and storage. Hence, finding ways to restore synaptic function can help restore learning and memory ability. Erythropoietin (EPO) has shown beneficial effects in the brain as a neuroprotector, improving affected learning, memory, and synaptic plasticity among other. In the present study, using the fimbria-fornix lesion model, we address the question whether the administration of erythropoietin restores the synaptic capacity to produce long-lasting increases in their transmission efficiency. A series of experiments was designed in which a control group of healthy young animals and one of injured young animals were formed. A subgroup of injured animals was injected with EPO or the vehicle in which the EPO is diluted (Veh). EPO or Veh was administered 15 min before LTP induction. Our data show that EPO produces a recovery in LTP in the group of fimbria-fornix lesioned animals, which show a severe impairment in the maintenance of LTP. Furthermore, LTP in the injured animals that received EPO was similar to that of the healthy control animals. LTP is widely accepted as a cellular mechanism of memory. Restoring LTP by EPO might be a potential tool for the treatment of memory disturbing diseases like Alzheimers disease. Ongoing clinical trials are evaluating a potential therapeutic effect of low sialic acid-EPO (NeuroEPO) on degenerative diseases.

Mammillary body abnormalities and cognitive outcomes in children cooled for neonatal encephalopathy.

AIM: To evaluate mammillary body abnormalities in school-age children without cerebral palsy treated with therapeutic hypothermia for neonatal hypoxic-ischaemic encephalopathy (cases) and matched controls, and associations with cognitive outcome, hippocampal volume, and diffusivity in the mammillothalamic tract (MTT) and fornix. METHOD: Mammillary body abnormalities were scored from T1-weighted magnetic resonance imaging (MRI) in 32 cases and 35 controls (median age [interquartile range] 7 years [6 years 7 months-7 years 7 months] and 7 years 4 months [6 years 7 months-7 years 7 months] respectively). Cognition was assessed using the Wechsler Intelligence Scale for Children, Fourth Edition. Hippocampal volume (normalized by total brain volume) was measured from T1-weighted MRI. Radial diffusivity and fractional anisotropy were measured in the MTT and fornix, from diffusion-weighted MRI using deterministic tractography. RESULTS: More cases than controls had mammillary body abnormalities (34% vs 0%; p < 0.001). Cases with abnormal mammillary bodies had lower processing speed (p = 0.016) and full-scale IQ (p = 0.028) than cases without abnormal mammillary bodies, and lower scores than controls in all cognitive domains (p < 0.05). Cases with abnormal mammillary bodies had smaller hippocampi (left p = 0.016; right p = 0.004) and increased radial diffusivity in the right MTT (p = 0.004) compared with cases without mammillary body abnormalities. INTERPRETATION: Cooled children with mammillary body abnormalities at school-age have reduced cognitive scores, smaller hippocampi, and altered MTT microstructure compared with those without mammillary body abnormalities, and matched controls. WHAT THIS PAPER ADDS: Cooled children are at higher risk of mammillary body abnormalities than controls. Abnormal mammillary bodies are associated with reduced cognitive scores and smaller hippocampi. Abnormal mammillary bodies are associated with altered mammillothalamic tract diffusivity.

Optimal deep brain stimulation sites and networks for stimulation of the fornix in Alzheimer's disease.

Deep brain stimulation (DBS) to the fornix is an investigational treatment for patients with mild Alzheimer's Disease. Outcomes from randomized clinical trials have shown that cognitive function improved in some patients but deteriorated in others. This could be explained by variance in electrode placement leading to differential engagement of neural circuits. To investigate this, we performed a post-hoc analysis on a multi-center cohort of 46 patients with DBS to the fornix (NCT00658125, NCT01608061). Using normative structural and functional connectivity data, we found that stimulation of the circuit of Papez and stria terminalis robustly associated with cognitive improvement (R = 0.53, p < 0.001). On a local level, the optimal stimulation site resided at the direct interface between these structures (R = 0.48, p < 0.001). Finally, modulating specific distributed brain networks related to memory accounted for optimal outcomes (R = 0.48, p < 0.001). Findings were robust to multiple cross-validation designs and may define an optimal network target that could refine DBS surgery and programming.

Deep brain stimulation of fornix for memory improvement in Alzheimer's disease: A critical review.

Memory reflects the brain function in encoding, storage and retrieval of the data or information, which is a fundamental ability for any live organism. The development of approaches to improve memory attracts much attention due to the underlying mechanistic insight and therapeutic potential to treat neurodegenerative diseases with memory loss, such as Alzheimer's disease (AD). Deep brain stimulation (DBS), a reversible, adjustable, and non-ablative therapy, has been shown to be safe and effective in many clinical trials for neurodegenerative and neuropsychiatric disorders. Among all potential regions with access to invasive electrodes, fornix is considered as it is the major afferent and efferent connection of the hippocampus known to be closely associated with learning and memory. Indeed, clinical trials have demonstrated that fornix DBS globally improved cognitive function in a subset of patients with AD, indicating fornix can serve as a potential target for neurosurgical intervention in treating memory impairment in AD. The present review aims to provide a better understanding of recent progresses in the application of fornix DBS for ameliorating memory impairments in AD patients.

Diffusion tensor tractography of the fornix in cerebral amyloid angiopathy, mild cognitive impairment and Alzheimer's disease.

PURPOSE: Cerebral amyloid angiopathy (CAA) is a common neuropathological finding and clinical entity that occurs independently and with co-existent Alzheimer's disease (AD) and small vessel disease. We compared diffusion tensor imaging (DTI) metrics of the fornix, the primary efferent tract of the hippocampus between CAA, AD and Mild Cognitive Impairment (MCI) and healthy controls. METHODS: Sixty-eight healthy controls, 32 CAA, 21 AD, and 26 MCI patients were recruited at two centers. Diffusion tensor images were acquired at 3 T with high spatial resolution and fluid-attenuated inversion recovery (FLAIR) to suppress cerebrospinal fluid (CSF) and minimize partial volume effects on the fornix. The fornix was delineated with deterministic tractography to yield mean diffusivity (MD), axial diffusivity (AXD), radial diffusivity (RD), fractional anisotropy (FA) and tract volume. Volumetric measurements of the hippocampus, thalamus, and lateral ventricles were obtained using T1-weighted MRI. RESULTS: Diffusivity (MD, AXD, and RD) of the fornix was highest in AD followed by CAA compared to controls; the MCI group was not significantly different from controls. FA was similar between groups. Fornix tract volume was âˆ¼ 30% lower for all three patient groups compared to controls, but not significantly different between the patient groups. Thalamic and hippocampal volumes were preserved in CAA, but lower in AD and MCI compared to controls. Lateral ventricular volumes were increased in CAA, AD and MCI. Global cognition, memory, and executive function all correlated negatively with fornix diffusivity across the combined clinical group. CONCLUSION: There were significant diffusion changes of the fornix in CAA, AD and MCI compared to controls, despite relatively intact thalamic and hippocampal volumes in CAA, suggesting the mechanisms for fornix diffusion abnormalities may differ in CAA compared to AD and MCI.

DWI Hyperintensity in the Fornix Fimbria on MRI in Children.

BACKGROUND AND PURPOSE: The fornix-fimbria complex is mainly involved in emotions and memory. In brain MR imaging studies of young children, we have occasionally noted DWI hyperintensity in this region. The significance of this finding remains unclear. This study evaluated the DWI signal in the fornix-fimbria complex of children 0-2 years of age, including the frequency of signal hyperintensity and clinical context. MATERIALS AND METHODS: Brain MR imaging of 714 children 0-2 years of age (mean, 11 months), performed between September 2018 and May 2021, was reviewed and evaluated for DWI signal changes in the fornix-fimbria. All children with available MR imaging studies including DWI were included. Children with poor image quality, poor visualization of the fornix-fimbria region, and missing medical data were excluded. Additional imaging findings were also evaluated. Demographic data were retrieved from the medical files. We compared the ADC values of the fimbria and fornix between children with and without signal changes. The unpaired 2-tailed Student t test and χ2 test were used for statistical analysis. RESULTS: DWI signal hyperintensity of the Fornix-fimbria complex was noted in 53 (7.4%) children (mean age, 10 months). Their mean ADC values were significantly lower than those of the children with normal DWI findings (P < .05). About half of the children had otherwise normal MR imaging findings. When detected, the most common abnormality was parenchymal volume loss (15%). The most common indication for imaging was seizures (26.5%). CONCLUSIONS: DWI hyperintensity in the fornix-fimbria complex was detected in 7.4% of children 0-2 years of age. The etiology is not entirely clear, possibly reflecting a transient phenomenon.

The fornix supports episodic memory during childhood.

Episodic memory relies on the coordination of widespread brain regions that reconstruct spatiotemporal details of an episode. These topologically dispersed brain regions can rapidly communicate through structural pathways. Research in animal and human lesion studies implicate the fornix-the major output pathway of the hippocampus-in supporting various aspects of episodic memory. Because episodic memory undergoes marked changes in early childhood, we tested the link between the fornix and episodic memory in an age window of robust memory development (ages 4-8 years). Children were tested on the stories subtest from the Children's Memory Scale, a temporal order memory task, and a source memory task. Fornix streamlines were reconstructed using probabilistic tractography to estimate fornix microstructure. In addition, we measured fornix macrostructure and computed free water. To assess selectivity of our findings, we also reconstructed the uncinate fasciculus. Findings show that children's memory increases from ages 4 to 8 and that fornix micro- and macrostructure increases between ages 4 and 8. Children's memory performance across nearly every memory task correlated with individual differences in fornix, but not uncinate fasciculus, white matter. These findings suggest that the fornix plays an important role in supporting the development of episodic memory, and potentially semantic memory, in early childhood.

Bilateral fornix infarction presented with acute amnesia: case report.

Acute episodes of amnestic syndrome can be a challenging diagnostic problem. Except for nonvascular etiology, thalamic strokes or infarction involving several temporal lobe structures has been reported in earlier cases. The authors report a patient who suddenly developed memory loss without any other focal neurologic deficits. Brain magnetic resonance imaging (MRI) with diffusion-weighted imaging (DWI) performed 1 day after onset revealed acute infarction involving the bilateral fornix column and the genu of corpus callosum. Because simple fornix infarcts often have no obvious positive neurological signs, most of the related manifestations were provided by family members, are easy to be diagnosed falsely, and missed in clinical areas, we suggest that bilateral fornix infarction should be considered in the diagnosis of an acute onset amnestic syndrome.

Protocol for deep brain stimulation in the fimbria-fornix of freely moving mice.

Deep brain stimulation (DBS) entails neurosurgery to implant electrodes in specific brain structures to modulate the behavior of a particular neural circuit. DBS is best known for treating advanced Parkinson disease and can potentially be applicable to other motor and even cognitive dysfunctions. Here, we describe a detailed protocol allowing for electrode preparation, surgical procedures, stimulation delivery, and field potential recordings in both anesthetized and behaving mice, and the benefit evaluation of DBS at the fimbria-fornix by using a fear conditioning test. For complete details on the use and execution of this protocol, please refer to Hao et al. (2015).

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.