Mammillothalamic Tract Lesions Research Articles

Anterior thalamic nuclei neurons sustain memory.

A hippocampal-diencephalic-cortical network supports memory function. The anterior thalamic nuclei (ATN) form a key anatomical hub within this system. Consistent with this, injury to the mammillary body-ATN axis is associated with examples of clinical amnesia. However, there is only limited and indirect support that the output of ATN neurons actively enhances memory. Here, in rats, we first showed that mammillothalamic tract (MTT) lesions caused a persistent impairment in spatial working memory. MTT lesions also reduced rhythmic electrical activity across the memory system. Next, we introduced 8.5 Hz optogenetic theta-burst stimulation of the ATN glutamatergic neurons. The exogenously-triggered, regular pattern of stimulation produced an acute and substantial improvement of spatial working memory in rats with MTT lesions and enhanced rhythmic electrical activity. Neither behaviour nor rhythmic activity was affected by endogenous stimulation derived from the dorsal hippocampus. Analysis of immediate early gene activity, after the rats foraged for food in an open field, showed that exogenously-triggered ATN stimulation also increased Zif268 expression across memory-related structures. These findings provide clear evidence that increased ATN neuronal activity supports memory. They suggest that ATN-focused gene therapy may be feasible to counter clinical amnesia associated with dysfunction in the mammillary body-ATN axis.

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.

The importance of mammillary body efferents for recency memory: towards a better understanding of diencephalic amnesia

Despite being historically one of the first brain regions linked to memory loss, there remains controversy over the core features of diencephalic amnesia as well as the critical site for amnesia to occur. The mammillary bodies and thalamus appear to be the primary locus of pathology in the cases of diencephalic amnesia, but the picture is complicated by the lack of patients with circumscribed damage. Impaired temporal memory is a consistent neuropsychological finding in Korsakoff syndrome patients, but again, it is unclear whether this deficit is attributable to pathology within the diencephalon or concomitant frontal lobe dysfunction. To address these issues, we used an animal model of diencephalic amnesia and examined the effect of mammillothalamic tract lesions on tests of recency memory. The mammillothalamic tract lesions severely disrupted recency judgements involving multiple items but left intact both recency and familiarity judgements for single items. Subsequently, we used disconnection procedures to assess whether this deficit reflects the indirect involvement of the prefrontal cortex. Crossed-lesion rats, with unilateral lesions of the mammillothalamic tract and medial prefrontal cortex in contralateral hemispheres, were unimpaired on the same recency tests. These results provide the first evidence for the selective importance of mammillary body efferents for recency memory. Moreover, this contribution to recency memory is independent of the prefrontal cortex. More broadly, these findings identify how specific diencephalic structures are vital for key elements of event memory.

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.

Selective disconnection of the hippocampal formation projections to the mammillary bodies produces only mild deficits on spatial memory tasks: Implications for fornix function

It is now clear that the integrity of the fornix is important for normal mnemonic function. The fornix, however, is a major white matter tract, carrying numerous hippocampal formation afferents and efferents, and it is not known which specific components support memory processes. Established theories of extended hippocampal function emphasize the sequential pathway from the hippocampal formation (i.e., subicular complex) to the mammillary bodies and, thence, to the anterior thalamus, as pathology in each of these structures is implicated in anterograde amnesia in humans and spatial memory deficits in rats. The specific importance of the hippocampal formation projections that just innervate the mammillary bodies has, however, never been tested. This study isolated these specific projections in the rat by selectively cutting the descending component of the postcommissural fornix. Two successive, cohorts of rats with these tract lesions were tested on working memory tasks in the water-maze, T-maze, and radial-arm maze. Disconnecting the descending postcommissural fornix had only a mild effect or sometimes no apparent effect on the performance of these spatial memory tasks, even though tracing experiments confirmed the loss of hippocampal formation-mammillary projections. One implication is that the spatial deficits found in rats following standard fornix lesions are only partly attributable to the loss of projections from the hippocampal formation to the mammillary bodies. Perhaps more surprising, the behavioral impact of cutting the descending postcommissural fornix in rats appeared appreciably less than the effect of either mammillary body or mammillothalamic tract lesions. The present experiments show that the mammillary bodies can still effectively support spatial memory in the absence of their dense subicular complex inputs, so revealing the importance of the other afferents for sustaining mammillary body function. This new evidence for independent functions shows that the mammillary bodies are more than just a hippocampal relay.

Mammillothalamic tract lesions disrupt dead reckoning in the rat

Debate surrounds the role of the limbic system structures' contribution to spatial orientation. The results from previous studies have supported a role for the mammillary bodies and their projections to the anterior thalamus in rapid encoding of relationships among environmental cues; however, this work is based on behavioral tasks in which environmental and self-movement cues could not be dissociated. The present study examines the effects of mammillothalamic tract lesions on spatial orientation in the food hoarding paradigm and the water maze. Although the food hoarding paradigm dissociates the use of environmental and self-movement cues, both sources of information are available to guide performance in the water maze. Mammillothalamic tract lesions selectively impaired performance on both tasks. These impairments are interpreted as providing further evidence for the role of limbic system structures in processing self-movement cues.

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.

Hippocampal, retrosplenial, and prefrontal hypoactivity in a model of diencephalic amnesia: Evidence towards an interdependent subcortical‐cortical memory network

The medial diencephalon is vital for memory, but it is not known why. The present study tested between the predictions of current hypotheses as to why this region is critical for memory. Lesions were made in the rat mammillothalamic tract, the only diencephalic structure consistently associated with amnesia in humans after ischemia. Decreased activity, as measured by immediate-early gene expression (c-fos), was found in three key sites associated with memory function: the hippocampus, the prefrontal cortex, and the retrosplenial cortex. The specificity of these changes was confirmed by the qualitatively different patterns of immediately-early gene changes seen after amygdala lesions, e.g., hypoactivity in the hippocampus and retrosplenial cortex following mammillothalamic tract lesions but not following amygdala lesions. The mammillothalamic lesion results unify substrates linked to diencephalic and temporal lobe amnesia, and thereby support a new account of diencephalic amnesia that emphasizes multiple dysfunctions across hippocampal, retrosplenial, and prefrontal areas. This account suggests a role for the mammillary bodies that is independent of their hippocampal inputs.

Evidence of a Spatial Encoding Deficit in Rats with Lesions of the Mammillary Bodies or Mammillothalamic Tract

The present study sought to identify the role of the mammillary bodies and their projections to the anterior thalamic nuclei for spatial memory. Rats with either selective, neurotoxic mammillary body lesions or discrete mammillothalamic tract lesions were tested on various spatial working memory tasks. Tests using the T-maze, radial-arm maze, and water maze were manipulated to compare three possible theories of mammillary body function by increasing proactive interference, increasing retention interval, and taxing the rapid processing of novel spatial stimuli. On T-maze alternation and radial-arm maze tasks, both lesion groups were initially impaired but seemed to recover. Transfer tests revealed, however, a more permanent change in performance, suggesting a failure to use distal (allocentric) cues. Consistent with this, both groups were also impaired at matching-to-place in the water maze and showed little improvement with practice. Nevertheless, once the lesion groups had been trained on a task, they were not affected differentially either by an increase of proactive interference or by retention intervals of up to 30 min. Although both mammillary body and mammillothalamic tract lesions resulted in similar impairments, the mammillothalamic tract group was the more affected when acquiring new spatial information. Together, these results suggest that mammillary body damage causes an encoding deficit when learning new spatial tasks, resulting in a suboptimal mode of performance, which may reflect a loss of directional heading information.

Retention of choice behavior in rats following mammillothalamic tractotomy☆

In Experiment 1 mammillothalamic tract (MTT) lesions in rat produced no change in the performance of a preoperatively acquired contingent (successive) brightness discrimination motivated by hunger. Freezing, assessed in an unavoidable shock situation, and passive avoidance were also unaffected. In Experiment 2 comparable MTT lesions produced significant (p < 0.03) decrements in retention of shock avoidance behavior, yet had no effect on choice behavior once the rat started running. Thus, it appears that the effect of mammillothalamic tractotomy on avoidance behavior is not attributable to a direct increase in freezing or to a loss in the retention of the ability to make difficult discriminations per se.

Role of freezing and fear in avoidance decrements following mammillothalamic tractotomy in cat: II. Appetitively motivated behavior

Although previous work (Krieckhaus, 1964a; Krieckhaus & Chi, 1966) suggests that it is unlikely that the avoidance decrements following lesions of the mammillothalamic tract (MTT) are attributable to increased freezing behavior, in each case evaluation of freezing was confounded with concomitant changes in avoidance behavior. In the present experiment, freezing following MTT lesions was evaluated independently of avoidance behavior by using either the conditioned emotional response (CER) or an appetitively motivated visual discrimination in which the incorrect response was punished. In neither case was there any indication of increases in freezing or other signs of fear following lesions of the MTT. We thus conclude that the reported increases in freezing behavior following MTT lesions are a result of rather than a cause of a primary decrement in avoidance behavior.