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.

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.

Cortical deactivation induced by subcortical network dysfunction in limbic seizures.

Normal human consciousness may be impaired by two possible routes: direct reduced function in widespread cortical regions or indirect disruption of subcortical activating systems. The route through which temporal lobe limbic seizures impair consciousness is not known. We recently developed an animal model that, like human limbic seizures, exhibits neocortical deactivation including cortical slow waves and reduced cortical cerebral blood flow (CBF). We now find through functional magnetic resonance imaging (fMRI) that electrically stimulated hippocampal seizures in rats cause increased activity in subcortical structures including the septal area and mediodorsal thalamus, along with reduced activity in frontal, cingulate, and retrosplenial cortex. Direct recordings from the hippocampus, septum, and medial thalamus demonstrated fast poly-spike activity associated with increased neuronal firing and CBF, whereas frontal cortex showed slow oscillations with decreased neuronal firing and CBF. Stimulation of septal area, but not hippocampus or medial thalamus, in the absence of a seizure resulted in cortical deactivation with slow oscillations and behavioral arrest, resembling changes seen during limbic seizures. Transecting the fornix, the major route from hippocampus to subcortical structures, abolished the negative cortical and behavioral effects of seizures. Cortical slow oscillations and behavioral arrest could be reconstituted in fornix-lesioned animals by inducing synchronous activity in the hippocampus and septal area, implying involvement of a downstream region converged on by both structures. These findings suggest that limbic seizures may cause neocortical deactivation indirectly, through impaired subcortical function. If confirmed, subcortical networks may represent a target for therapies aimed at preserving consciousness in human temporal lobe seizures.

Direct, complex effects of estrogens on basal forebrain cholinergic neurons.

Although controversial, estrogens remain one of the few agents purported to influence the incidence of Alzheimer's disease and one of their postulated mechanisms of action is their effects on basal forebrain cholinergic neurons. However, it is unclear whether the responses of cholinergic neurons to estrogens are direct or mediated via the retrograde influences of neurotrophins, known to be induced by estrogens in the hippocampus and neocortex. In the present study, we explore the issue of the primary site of action of estrogens by studying the regulation of expression of genes that characterize mature cholinergic neurons, i.e., choline acetyltransferase, trkA, and p75(NTR) in the medial septum and the nucleus basalis complex. In parallel, we study the hippocampal expression of NGF, BDNF, and NT-3, i.e., neurotrophins with known trophic roles on cholinergic neurons. Gene expression is studied by RT-PCR in ovariectomized female rats with and without estrogen supplementation within the physiological estradiol range and in rats with complete fimbria-fornix transactions treated with estrogen or vehicle. To clarify mechanisms of estrogen transduction in cholinergic neurons, we study the effects of estrogen treatment on fimbria-fornix-lesioned mice with genetic ablations of ER subtypes alpha and beta. The results of the present study suggest that, while estrogens do regulate BDNF expression in the hippocampus and neocortex, they also exert stimulatory non-trophic effects on basal forebrain cholinergic neurons, primarily on ChAT expression. Cholinergic neurons retain their ability to respond to estrogens after their complete separation from the hippocampus. The elimination of ERalpha alters significantly the phenotypic responsiveness of cholinergic neurons to estrogens, whereas elimination of ERbeta appears to have no effect. Our findings support the idea that estrogens directly enhance cholinergic neuron function and that ERalpha plays a significant role in transducing these regulatory effects.

Transgenic AD model mice, effects of potential anti-AD treatments on inflammation and pathology.

The extracellular deposition of amyloid (A) peptides in plaques, and neurofibrillary tangles are the two characteristic pathological features of Alzheimer's disease (AD). Plaques are surrounded by activated astrocytes and microglia, to study the relation between amyloid neuropathology and inflammation, we examined the changes in amyloid pathology in the hippocampus following three different treatments aimed at reducing the amyloid burden. (1) To investigate the effects of long-term cholinergic deafferentation, we lesioned the fimbria-fornix pathway in our AD-model mice at 7 months of age, and 11 months post-lesion the mice were sacrificed for histopathological analysis. The fimbria-fornix transection resulted in a substantial depletion of cholinergic markers in the hippocampus, but the lesion did not result in an alteration in hippocampal A deposition and inflammation (i.e., numbers or staining density of astrocytes and microglia). (2) To investigate the effects of estrogen, we ovariectomized mice and treated them with estrogen (sham-lesion, zero dose, low dose, and high dose) and studied the pathology at different postsurgery intervals. Estrogen depletion (i.e., ovariectomy) or estrogen replacement did not affect A deposition or inflammation at any time point. (3) In the final studies, we treated mice with flurbiprofen and an NO-donating derivative of flurbiprofen (HCT 1026) for several months (from 6 till 14 months of age), and studied the A pathology and inflammation in the brain. Sham treatment, flurbiprofen, and the low-dose HCT 1026 did not affect pathology; however, a higher dose of HCT 1026 reduced both A load and amount of microglial activation surrounding plaques.

Fornix lesions impair context-related cingulothalamic neuronal patterns and concurrent discrimination learning in rabbits (Oryctolagus cuniculus).

Cingulothalamic neurons develop topographic patterns of cue-elicited neuronal activity during discrimination learning. These patterns are context-related and are degraded by hippocampal lesions, suggesting that hippocampal modulation of cingulothalamic activity results in the expression of the patterns, which could promote the retrieval of context-appropriate responses and memories. This hypothesis was tested by training rabbits (Oryctolagus cuniculus) with fornix lesions concurrently on two discrimination tasks (approach and avoidance) in different contexts. Because the same conditioned stimuli were used for both tasks, contextual information was critical for overcoming intertask interference during concurrent task acquisition. The lesions degraded the topographic patterns and significantly impaired concurrent learning, suggesting that hippocampal-cingulothalamic interactions and the resulting topographic patterns are critical for processing contextual information needed to defeat interference.

Heavily T2-weighted MR imaging of white matter tracts in the hypothalamus: normal and pathologic demonstrations.

BACKGROUND AND PURPOSE: The MR appearance of white matter tracts in the hypothalamus and the role of the hypothalamus as a memory mechanism have not been sufficiently described in clinical settings. Heavily T2-weighted black-and-white reversed (T2R) images were assessed to reveal their visualization and clinical significance. METHODS: One hundred healthy subjects and three patients with hypothalamic lesions underwent fast spin-echo MR imaging to reveal the postcommissural fornix (PF) and mammillothalamic tract (MT). RESULTS: The PF was identifiable in axial and/or coronal sections in all healthy subjects. No remarkable asymmetry of its size or course was evident. Both anteroposterior and vertical dimensions ranged from 10.5 to 14 mm. The MT was visible in one or two axial sections above the mammillary body in 64% of healthy subjects and in a coronal section in 36%. Two patients with glioblastoma multiforme and lacunar infarct at the hypothalamus presented with anterograde amnesia; T2R imaging revealed involvement of both the PF and MT. The third patient had a suprasellar craniopharyngioma with PF injury sparing the MT resulting from surgical manipulation and was free of memory deficit. Anterograde amnesia was evident only when both the PF and MT were injured. CONCLUSION: T2R images have made a high rate of detection of the PF and MT possible and could provide a more detailed correlation of hypothalamic neuroanatomy and memory mechanism in clinical settings.

The effects of hippocampal and fimbria-fornix lesions on prepulse inhibition.

The present experiments tested the effects of conventional (dorsal aspiration and electrolytic) and excitotoxic (N-methyl-D-aspartate [NMDA]) hippocampal lesions and fimbria-fornix (FF) transection on prepulse inhibition (PPI) of startle response and on open-field activity. Activity was increased by FF transection and by conventional but not excitotoxic hippocampal lesions; complete NMDA lesion increased amphetamine-induced activity. Whereas dorsal hippocampal aspiration lesion disrupted PPI, the phenomenon was not affected by dorsal hippocampal electrolytic lesion, partial or complete excitotoxic (NMDA) hippocampal lesions, or complete FF transection, which interrupted the cholinergic input to the hippocampus as well as the hippocampal-subicular input to the nucleus accumbens. Systemic apomorphine disrupted PPI in both FF-transected rats and their controls. It is suggested that the hippocampus is essential for PPI disruption rather than for PPI expression.