Mammillothalamic Disconnection Alters Hippocampocortical Oscillatory Activity and Microstructure: Implications for Diencephalic Amnesia

Abstract

Diencephalic amnesia can be as debilitating as the more commonly known temporal lobe amnesia, yet the precise contribution of diencephalic structures to memory processes remains elusive. Across four cohorts of male rats, we used discrete lesions of the mammillothalamic tract to model aspects of diencephalic amnesia and assessed the impact of these lesions on multiple measures of activity and plasticity within the hippocampus and retrosplenial cortex. Lesions of the mammillothalamic tract had widespread indirect effects on hippocampocortical oscillatory activity within both theta and gamma bands. Both within-region oscillatory activity and cross-regional synchrony were altered. The network changes were state-dependent, displaying different profiles during locomotion and paradoxical sleep. Consistent with the associations between oscillatory activity and plasticity, complementary analyses using several convergent approaches revealed microstructural changes, which appeared to reflect a suppression of learning-induced plasticity in lesioned animals. Together, these combined findings suggest a mechanism by which damage to the medial diencephalon can impact upon learning and memory processes, highlighting an important role for the mammillary bodies in the coordination of hippocampocortical activity. SIGNIFICANCE STATEMENT Information flow within the Papez circuit is critical to memory. Damage to ascending mammillothalamic projections has consistently been linked to amnesia in humans and spatial memory deficits in animal models. Here we report on the changes in hippocampocortical oscillatory dynamics that result from chronic lesions of the mammillothalamic tract and demonstrate, for the first time, that the mammillary bodies, independently of the supramammillary region, contribute to frequency modulation of hippocampocortical theta oscillations. Consistent with the associations between oscillatory activity and plasticity, the lesions also result in a suppression of learning-induced plasticity. Together, these data support new functional models whereby mammillary bodies are important for coordinating hippocampocortical activity rather than simply being a relay of hippocampal information as previously assumed.

The retrosplenial cortex and long-term spatial memory: from the cell to the network

“…These studies revealed RSC engagement during the expression [ 31 ] and the consolidation of spatial memory task [ 32 ]; however, RSC is not differentially involved when performing the same task in a novel room or with a novel configuration of spatial cues, unlike hippocampus [ 31 , 33 ]. Again, this fits with the concept that RSC is not engaged in the processing of novel spatial cues [ 23 , 29 •• ]. The resolution of IEG imaging enables analysis of subregions within RSC and this has provided additional evidence for functional dissociations within RSC: granular RSC is engaged in spatial working memory in both the light and the dark while dysgranular RSC is selectively involved in the light, that is, when visual cues are available [ 34 ].…”

“…Our group recently employed diffusion tensor imaging (DTI) to investigate changes in the microstructure of grey matter areas involved during spatial learning [ 23 ] ( Figure 2 ). DTI measures tissue inhomogeneity resulting from the asymmetric movement of water molecules and changes to some of its metrics can capture plastic events in both humans and rodents [ 24 , 25 , 26 ].…”

“…A few studies have carried out simultaneous electrophysiological recordings of RSC and the hippocampus to examine the interplay between these structures. We and others have identified state-dependent effects on cross-frequency modulation within RSC and coherence between RSC and hippocampus [ 23 , 46 ]. The interactions between RSC and hippocampus during REM sleep may be particularly relevant for the RSC’s role in consolidation.…”

Signal Change in the Mammillary Bodies after Perinatal Asphyxia

“…Given the importance of the MBs for episodic memory, 32 it is likely that MB pathology in patients with HIE contributes to memory impairment that can be associated with this patient group. However, the concomitant hippocampal damage makes it difficult to attribute specific impairment to the MBs.…”

Extensive long-term verbal memory training is associated with brain plasticity

“…The thalamic nuclei are also major components of the Papez circuit, as well as of the neural circuits responsible for specific categories of learning and memory 22 , 23 . The mammillothalamic tract lesion induce memory impairments, leading to amnesia 24 – 26 . Damages within this region are associated with Korsakoff syndrome, a chronic memory disorder 27 , 28 .…”