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.HighlightsThe mammillothalamic tract (MTT) supports neural activity in an extended memory system.Optogenetic activation of neurons in the anterior thalamus acutely improves memory after MTT lesions.Rescued memory associates with system-wide neuronal activation and enhanced EEG.Anterior thalamus actively sustains memory and is a feasible therapeutic target.Abstract FigureOptostimulation of anterior thalamus restores memory function after MTT lesionsCreated with BioRender.com

BIFURCATING NEURONS IN THE ANTERIOR THALAMIC NUCLEI

The anterior thalamic nuclei (ATN) form a nodal point within a hippocampal-cingulate-diencephalic memory system. ATN projections to different brain structures are conventionally viewed as distinct, but ATN neurons may send collaterals to multiple structures. The anteromedial subregion (AM) is the primary source of efferents to the medial prefrontal cortex (mPFC). Using a dual-retrograde neurotracer strategy, we discovered bifurcating AM neurons for tracers placed in the mPFC when paired with other regions. A semi-quantitative analysis found a high proportion of AM neurons (~36%) showed collateral projections when the mPFC was paired with dorsal subiculum (dSub); 20% were evident for mPFC paired with caudal retrosplenial cortex (cRSC); and 6% was found for mPFC and ventral hippocampal formation (vHF). About 10% of bifurcating AM neurons was also identified when the mPFC was not included, that is, for cRSC with dSub, and cRSC with vHF. Similar percentages of bifurcating neurons were also found within the anterior region of the adjacent nucleus reuniens (Re). The high frequency of bifurcating neurons suggests a new perspective for ATN function. These neurons would facilitate direct coordination among distal neural ensembles to support episodic memory and may explain why the ATN is a critical region for diencephalic amnesia.

Anterior thalamic nuclei: A critical substrate for non-spatial paired-associate memory

The anterior thalamic nuclei (ATN), a central node in a complex memory system, process spatial and temporal memory. Here, we show that ATN lesions do not affect acquisition of a simple odour discrimination or a simple object discrimination in a runway apparatus. The same procedures were used to test learning of an arbitrary association between non-spatial object-odour pairings (A+X or B+Y were rewarded; but not A+Y or B+X). If ATN lesions recapitulate hippocampal function, specifically CA1 function, then they should disrupt acquisition only when an explicit delay (i.e., a 10-second trace) is inserted between the odour and object. Acquisition was completely abolished by ATN lesions, irrespective of the presence of the temporal trace, and despite extensive training (50x12-trial sessions). Faster acquisition with the 10-second trace was found in the sham-lesion rats. During recall, 5 days after criterion, sham rats but not ATN-lesion rats showed elevated Zif268 expression in hippocampal CA1 for the trace compared to no-trace condition; both sham and lesion rats tested in the trace condition showed increased IEG expression in the superficial layers of the prefrontal cortex and retrosplenial cortex. ATN lesions markedly reduced Zif268 expression in the prefrontal cortex and retrosplenial cortex. This is the first evidence that ATN lesions impair non-spatial paired-associate tasks. The findings suggest that the ATN influence memory beyond time and space, and constitute a critical neural structure for learning arbitrary associations even in the task version that is not disrupted by hippocampal lesions.