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.

Lesions of the head direction cell system impair direction discrimination.

Previous results suggest that directional information from the head direction cell circuit may inform hippocampal place cell firing when an animal is confronted with visually identical environments. To investigate whether such information might also be essential for spatial behavior, we tested adult, male Lister Hooded rats that had received either bilateral lateral mammillary nuclei (LMN) lesions or sham lesions on a four-way, conditional odor-location discrimination in compartments arranged at 60° to one another. We found that significantly fewer rats in the LMN lesion group were able to learn the task compared to the Sham group. We also found that the extent of the behavioral impairment was highly correlated with the degree of tissue loss in the LMN resulting from the lesion. Animals with LMN lesions were also impaired in a nonmatching-to-sample task in a T maze, and the extent of impairment likewise depended on the extent of the lesion. Performance in the odor-location and T-maze tasks was not affected by tissue loss in the medial mammillary nuclei. Together, these results indicate that the LMN, a key node in the head direction circuit, is critical for solving a spatial task that requires a directional discrimination. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Anterior thalamic nuclei lesions have a greater impact than mammillothalamic tract lesions on the extended hippocampal system.

The anterior thalamic nuclei (ATN), mammillary bodies and their interconnecting fiber tract, the mammillothalamic tract (MTT), are important components of an extended hippocampal circuit for episodic memory. In humans, damage to the MTT or ATN in many disorders is associated with severe anterograde amnesia and it is assumed that their influence on memory is functionally equivalent. The relative influence of these two structures on memory has not, however, been assessed explicitly. Here, a direct comparison found that only ATN lesions impaired spatial reference memory in rats. ATN lesions produced more severe deficits on spatial working memory and reduced zif268 expression to a greater degree and in more corticolimbic sites than did MTT lesions. Conversely, MTT lesions reduced NeuN cell counts in all three subregions of the MB to a greater extent than did ATN lesions, so their relative impact cannot be explained by retrograde neuropathology of the MB. Hence ATN injury causes a more critical dysfunction than would be expected by an emphasis on the indirect influence of brainstem inputs to the extended memory system. The greater ATN lesion deficits found here may represent the consequence of disruption to the direct connections of the ATN with both hippocampal and cortical sites.

Comparable reduction in Zif268 levels and cytochrome oxidase activity in the retrosplenial cortex following mammillothalamic tract lesions.

Damage to the mammillothalamic tract (MTT) produces memory impairments in both humans and rats, yet it is still not clear why this diencephalic pathway is vital for memory. One suggestion is that it is an important route for midbrain inputs to reach a wider cortical and subcortical network that supports memory. Consistent with this idea, MTT lesions produce widespread hypoactivity in distal brain regions as measured by the immediate-early gene, c-fos. To determine whether these findings were selective to c-fos or reflected more general changes in neuronal function, we assessed the effects of MTT lesions on the expression of the immediate-early gene protein, Zif268 and the metabolic marker, cytochrome oxidase, in the retrosplenial cortex and hippocampus. The lesions decreased levels of both activity markers in the superficial and deep layers of the retrosplenial cortex in both its granular and dysgranular subregions. In contrast, no significant changes were observed in the hippocampus, despite the MTT-lesioned animals showing marked impairments on T-maze alternation. These findings are consistent with MTT lesions providing important, indirect inputs for normal retrosplenial cortex functioning. These distal functional changes may contribute to the memory impairments observed after MTT lesions.

Acetylcholine facilitates recovery of episodic memory after brain damage.

Episodic memory depends on a network of interconnected brain structures including the inferior temporal cortex, hippocampus, fornix, and mammillary bodies. We have previously shown that a moderate episodic memory impairment in monkeys with transection of the fornix is exacerbated by prior depletion of acetylcholine from inferotemporal cortex, despite the fact that depletion of acetylcholine from inferotemporal cortex on its own has no effect on episodic memory. Here we show that this effect occurs because inferotemporal acetylcholine facilitates recovery of function following structural damage within the neural circuit for episodic memory. Episodic memory impairment caused by lesions of the mammillary bodies, like fornix transection, was exacerbated by prior removal of temporal cortical acetylcholine. However, removing temporal cortical acetylcholine after the lesion of the fornix or mammillary bodies did not increase the severity of the impairment. This lesion order effect suggests that acetylcholine within the inferior temporal cortex ordinarily facilitates functional recovery after structural lesions that impair episodic memory. In the absence of acetylcholine innervation to inferotemporal cortex, this recovery is impaired and the amnesia caused by the structural lesion is more severe. These results suggest that humans with loss of cortical acetylcholine function, for example in Alzheimer's disease, may be less able to adapt to memory impairments caused by structural neuronal damage to areas in the network important for episodic memory.

A role for the head-direction system in geometric learning.

Several recent models of episodic memory have highlighted a potential contribution from the head-direction system; there is, however, surprisingly little known about the behavioural effects of selective lesions within the head-direction system. To address this issue, and determine what aspects of spatial memory are dependent on the head-direction system, rats with selective lateral mammillary body lesions were tested on tasks that required the use of specific spatial cues, including direction, visual allocentric, and geometric cues. Animals were first tested on a modified version of the T-maze alternation task that enabled the systematic removal of intramaze and visual allocentric cues. Rats were next tested on a geometric task that required the use of the shape of the environment to locate a hidden platform in the water-maze. The lesion rats were impaired on one stage of the T-maze alternation task and on the acquisition of the geometric task; these results are consistent with the head-direction system contributing to the processing of, and/or subsequent use, of visual allocentric and geometric cues. From the pattern of impairments it also appears that, with training, rats with lateral mammillary body lesions are able to recruit other navigational systems or that there is some degree of redundancy within the head-direction system.

Re-evaluating the role of the mammillary bodies in memory.

Although the mammillary bodies were among the first brain regions to be implicated in amnesia, the functional importance of this structure for memory has been questioned over the intervening years. Recent patient studies have, however, re-established the mammillary bodies, and their projections to the anterior thalamus via the mammillothalamic tract, as being crucial for recollective memory. Complementary animal research has also made substantial advances in recent years by determining the electrophysiological, neurochemical, anatomical and functional properties of the mammillary bodies. Mammillary body and mammillothalamic tract lesions in rats impair performance on a number of spatial memory tasks and these deficits are consistent with impoverished spatial encoding. The mammillary bodies have traditionally been considered a hippocampal relay which is consistent with the equivalent deficits seen following lesions of the mammillary bodies or their major efferents, the mammillothalamic tract. However, recent findings suggest that the mammillary bodies may have a role in memory that is independent of their hippocampal formation afferents; instead, the ventral tegmental nucleus of Gudden could be providing critical mammillary body inputs needed to support mnemonic processes. Finally, it is now apparent that the medial and lateral mammillary nuclei should be considered separately and initial research indicates that the medial mammillary nucleus is predominantly responsible for the spatial memory deficits following mammillary body lesions in rats.

Lesions of the mammillary body region severely disrupt the cortical head direction, but not place cell signal.

The rat limbic system contains a variety of location (place and grid) cells and directional (head direction; HD) cells, thought to be critical for navigation. The HD cells can be found throughout many portions of the hippocampal formation, as well as additional limbic cortical and subcortical regions. These HD-containing regions are generally strongly interconnected anatomically. Earlier work, along with theoretical considerations, suggest that despite the ubiquitous presence of HD cells, there may be a single region which is critical for the initial formation of this HD signal. Specifically, it has been suggested that the critical HD cell network resides in a reciprocal loop formed by the interconnected lateral mammillary nucleus and dorsal tegmental nucleus of Gudden. Unlike the HD cells, place cells have not been observed in subcortical structures. They are, however, found in various forms throughout much of the hippocampal formation. Theoretical accounts of the place cells suggest that they are partly dependent on a path integration process which is, in turn, dependent on the HD cells. According to the above reasoning, lesions of the mammillary bodies should completely eliminate both HD and place/grid cells in the hippocampal formation. Here, we tested for both HD and place cell activity in various hippocampal formation sub regions following lesions of the mammillary bodies. We found that these lesions caused nearly complete elimination of the HD cell signal, but left the place cell signal largely intact. Our interpretation of these findings is somewhat limited by the fact that we did not provide a thorough test of the path integration abilities of the post lesion place cells. These findings pose a challenge for current theoretical accounts of place and grid cells. They also help to explain the role played by the mammillary bodies in spatial learning and memory.

Hyperphagia and increased body weight induced by lesions of the ventral tuberomammillary system.

Individual lesions of the caudal (E1) or rostral (E2) ventral tuberomammillary nuclei induced hyperphagia in Wistar rats. The aim of the present study was to examine the additive or united effects of combined lesions of E1+E2 in food intake. E1+E2 lesions produced an immediate, potent and permanent hyperphagic response that was greater than that observed in groups with individual lesions (E1 or E2) during the 22-day observation period. Furthermore, at the end of this period (Days 17/22), the combined lesions induced a greater increase in body weight compared with groups with individual lesions. As previously reported, polydipsia is also induced by lesions of the ventral tuberomammillary subnuclei. However, in this case, responses of the individual polydipsic groups did not differ from those found in the E1+E2 ventral tuberomammillary group. These results are interpreted in terms of the hypothalamic systems involved in food and water intake.

Supramammillary and adjacent nuclei lesions impair spatial working memory and induce anxiolitic-like behavior.

The present study assesses the involvement of the supramammillary and adjacent nuclei in spatial memory and anxiety-like behaviors. Rats with electrolytic lesions in the supramammillary nucleus were pre- and post-operatively trained in two spatial memory tasks and two anxiety tasks. Spatial memory tasks were performed in an open field with seven different goal positions containing the reward. Anxiety-like behaviors were tested in the elevated T-maze. In the spatial reference memory task, neither lesioned nor sham-lesioned groups were impaired. In the working memory task, lesioned animals were permanently impaired in their ability to solve the delayed-matching-to-position task. This working memory deficit is not related to increased proactive interference. It could be related to impairment of the rats ability to reorganize spatial stimuli. Consequently, rats were not able to achieve an optimal performance level to solve spatial tasks with continuous changes in the place location. In the elevated T-maze, lesioned rats reduced passive avoidance response but no changes in the escape response were observed. These results suggest a clear involvement of the supramammillary nucleus in working memory and behavioral inhibition but not in either spatial reference memory or in escape responses.

Involvement of the supramammillary nucleus in aversive conditioning.

Mechanisms for the retention and retrieval of conditioned taste aversions (CTAs) have yet to be fully defined. The authors explored relevant subcortical forebrain regions by tracking the expression of immediate early genes, c-fos and zif268. The supramammillary nucleus (SuM) was activated following both viscerally based CTA and somatically based inhibitory avoidance (IA). Excitotoxic lesions of the SuM before conditioning caused no disruption of acquisition but accelerated the extinction of both the CTA and IA. In contrast, lesions after CTA conditioning did not impair retention or retrieval. The present study indicates that the SuM is activated by memory-elicited discomfort during retrieval, suggesting that it plays a role in resisting the extinction of a long-term aversive memory.

Inhibition of collagen IV deposition promotes regeneration of injured CNS axons.

Scarring impedes axon regrowth across the lesion site and is one major extrinsic constraint to effective regeneration in the adult mammalian central nervous system. In the present study we determined whether specific biochemical or immunochemical modulation of one major component of the scar, the basal membrane (BM), would provide a means to stimulate axon regeneration in the mechanically transected postcommissural fornix of the adult rat. Basal membrane developed within the first 2 weeks after transection in spatiotemporal coincidence with the abrupt growth arrest of spontaneously regrowing axons. Local injection of anticollagen IV antibodies or alpha, alpha'-dipyridyl, an inhibitor of collagen triple helix formation and synthesis, significantly reduced lesion-induced BM deposition. This treatment allowed massive axon elongation across the lesion site. Anterograde tracing provided unequivocal evidence that regenerating axons follow their original pathway, reinnervate the appropriate target, the mammillary body, and become remyelinated with compact myelin. Presynaptic electrophysiological recordings of regenerated fibre tracts showed recovery to nearly normal conduction properties. Our results indicate that lesion-induced BM is an impediment for successful axonal regeneration and its reduction is a prerequisite and sufficient condition for regrowing axons to cross the lesion site.

Effects of mammillary bodies and mediodorsal thalamic lesions on the acquisition and retention of a learning set in mice: paradoxical effect of the intersession interval.

The effects of ibotenic acid lesions of either the mediodorsal thalamus (MD) or the mammillary bodies (MB) on the acquisition and retention of a reversal learning set in a T-maze were studied in mice. Both the MB and MD lesions disrupted performance in this task, but only MD lesions slowed down the rate of learning, MD-lesioned subjects requiring more trials than the other two groups to master the discrimination at the end of the learning phase. Surprisingly, increasing the intersession interval from 24 h to 10 days totally alleviated the deficit of MD-subjects and even improved their performance as compared to the last (8th day) session. The overall results of the study show that both MD and MB lesions do not induce important learning deficits nor anterograde amnesia in the reversal learning set task.

[Primary/secondary characteristics of polydipsia induced by electrolytic lesion of the mammillary bodies]. / Estudio del carácter primario/secundario de la polidipsia inducida por lesión electrolítica de los cuerpos mamilares.

Rats with mammillary electrolytic lesions show a strong polydipsia and polyuria. This over-consumption may be primary or secondary to the polyuric effect. In this regard, mammillary lesioned rats excrete a greater amount of urine compared with control animals when matched in daily water consumption (partial water deprivation). Moreover, this abnormal water intake is significantly reversed by treatment with Pitressin, a vasopressin analogue. These results suggest that the polydipsia may be determined by the urinary water loss. However, when subjected to the bilateral ureter ligation, the experimental animals still outdrink the control ones, thus also suggesting a primary component of the polydipsia under study. The possible explanation of these components in relation to the mammillary polydipsia is discussed.

Dorsal thalamic lesion in a noted case of human memory dysfunction.

The extensively studied patient N.A. has had a severe verbal memory deficit since 1960, when he sustained a stab wound to the brain with a miniature fencing foil. His amnesia occurs in the absence of any other known cognitive defect. Recent CT scans have localized a lesion in the left dorsal thalamus of this patient in a position corresponding to the dorsomedial nucleus; there is no radiographic evidence of other damage in the diencephalon or cerebral cortex. The dorsomedial thalamus may be critical in the neuropathology of diencephalic amnesia and, in humans, may be required for normal memory functions.