Deconstructing the Direct Reciprocal Hippocampal-Anterior Thalamic Pathways for Spatial Learning

Abstract

The hippocampus is essential for normal memory but does not act in isolation. The anterior thalamic nuclei may represent one vital partner. Using DREADDs, the behavioral consequences of transiently disrupting anterior thalamic function was examined, followed by inactivation of the dorsal subiculum. Next, the anterograde transport of an adenoassociated virus expressing DREADDs was paired with localized intracerebral infusions of a ligand to target specific input pathways. In this way, the direct projections between the anterior thalamic nuclei and the dorsal hippocampal formation were inhibited, followed by separate inhibition of the dorsal subiculum projections to the anterior thalamic nuclei. To assay spatial working memory, all animals performed a reinforced T-maze alternation task, then a more challenging version that nullifies intra-maze cues. Across all four experiments, deficits emerged on the spatial alternation task that precluded the use of intra-maze cues. Inhibiting dorsal subiculum projections to the anterior thalamic nuclei produced the severest spatial working memory deficit. This deficit revealed the key contribution of dorsal subiculum projections to the anteromedial and anteroventral thalamic nuclei for the processing of allocentric information, projections not associated with head-direction information. The overall pattern of results provides consistent causal evidence of the twoway functional significance of direct hippocampal-anterior thalamic interactions for spatial processing. At the same time, these findings are consistent with hypotheses that these same, reciprocal interactions underlie the common core symptoms of temporal lobe and diencephalic anterograde amnesia. 3 3 Significance Statement It has long been conjectured that the anterior thalamic nuclei might be key partners with the hippocampal formation and that, respectively, they are principally responsible for diencephalic and temporal lobe amnesia. However, direct causal evidence for this functional relationship is lacking. Here, we examined the behavioral consequences of transiently silencing the direct reciprocal interconnections between these two brain regions on tests of spatial learning. Disrupting information flow from the hippocampal formation to the anterior thalamic nuclei and vice versa impaired performance on tests of spatial learning. By revealing the conjoint importance of hippocampal-anterior thalamic pathways, these findings help explain why pathology in either the medial diencephalon or the medial temporal lobes can result in profound anterograde amnesic syndromes.

Robust information routing by dorsal subiculum neurons

“…In contrast, inactivation of the distal SUB, but not the proximal SUB containing NAC-p neurons, has been shown to impair spatial working memory in a Morris water maze task (23). In addition, Nelson et al (67) found that the reciprocal connection between the SUB and anterior thalamic nuclei, including the AV, is required for a modified T-maze task, in which animals could not use intramaze cues. Collectively, while multiple SUB projections are recruited in spatial working memory tasks, their necessity appears to depend on various factors, including the type of behavioral task, task difficulty, delay length, and richness of available cues.…”

Anterior Thalamic Inputs Are Required for Subiculum Spatial Coding, with Associated Consequences for Hippocampal Spatial Memory

“…This network model suggests that the ATN are key structures within both diencephalic and temporal lobe memory systems ( Aggleton and Brown, 1999 ; Ranganath and Ritchey, 2012 ). In rodents, for instance, anterior thalamic lesions severely impair spatial learning, mirroring hippocampal damage ( Morris et al, 1982 ; Warburton and Aggleton, 1999 ; Moran and Dalrymple-Alford, 2003 ); moreover, disconnection studies suggest that the hippocampal formation and ATN are functionally interdependent ( Sutherland and Rodriguez, 1989 ; Shibata, 1993 ; Nelson et al, 2020 ).…”

Anterior thalamic stimulation improves working memory precision judgments

“…With dense and reciprocal connections with the hippocampus [13e15], and its involvement in cognitive function [15e17], the anterior nucleus of thalamus (ANT) has been suggested as an extended hippocampal system [18e20]. A rodent study found that disrupting information flow between the hippocampal and ANT impaired spatial working memory performance [21]. Electrical stimulation directly targeted to the hippocampus can disrupt memory performance [22,23].…”