Time to put the mammillothalamic pathway into context

Abstract

The medial diencephalon, in particular the mammillary bodies and anterior thalamic nuclei, has long been linked to memory and amnesia. The mammillary bodies provide a dense input into the anterior thalamic nuclei, via the mammillothalamic tract. In both animal models, and in patients, lesions of the mammillary bodies, mammillothalamic tract and anterior thalamic nuclei all produce severe impairments in temporal and contextual memory, yet it is uncertain why these regions are critical. Mounting evidence from electrophysiological and neural imaging studies suggests that mammillothalamic projections exercise considerable distal influence over thalamo-cortical and hippocampo-cortical interactions. Here, we outline how damage to the mammillary body-anterior thalamic axis, in both patients and animal models, disrupts behavioural performance on tasks that relate to contextual ("where") and temporal ("when") processing. Focusing on the medial mammillary nuclei as a possible 'theta-generator' (through their interconnections with the ventral tegmental nucleus of Gudden) we discuss how the mammillary body-anterior thalamic pathway may contribute to the mechanisms via which the hippocampus and neocortex encode representations of experience.

Keywords: Amnesia; Anterior thalamic nuclei; Diencephalon; Hippocampus; Mammillary bodies; Memory; Retrosplenial cortex.

Fig. 1

Main anatomical connections associated with the mammillary body-anterior thalamic pathway. The mammillary bodies receive topographically organised inputs from midbrain, subcortical, and cortical brain regions and project to the anterior thalamic nuclei. a, Anatomical connections of the medial mammillary nuclei. The principle output from the medial nuclei constitute topographical projections from pars medialis and pars lateralis sub-nuclei to the anteromedial and anteroventral thalamic nuclei, respectively. Hippocampal efferents derive predominantly from the dorsal, intermediate and ventral subiculum. The ventral tegmental nuclei of Gudden send a dense GABAergic projection to the medial mammillary bodies, reciprocated by medial mammillary projections. This recurrent circuit is thought to aid the generation of theta rhythmicity (see Section 3.1). b, Anatomical connections of the lateral mammillary nuclei. Reciprocal connections between the lateral mammillary bodies and the dorsal tegmental nuclei of Gudden constitute the generative pathway of the vestibular head direction system. Thalamic projections of the lateral mammillary nuclei are exclusively to the anterodorsal thalamic nuclei while hippocampal inputs to the lateral mammillary nuclei arise dominantly from the postsubiculum of the hippocampal formation. Dashed line in A represents a possible but unconfirmed projection (see Section 2.2.2). The connections depicted are for the rat; while the general pattern of connections is similar in the primate, there are some differences in specific subregion connectivity. CTX – cortex.

Fig. 2

Mammillothalamic lesions (MTT) result in temporal (a) and contextual (b) memory impairments. In object recency experiments (a), rats are trained to shuttle from end-to-end in a bow tie maze. In each end of the maze, a partition separates the two objects which are positioned over a reward. On visits to each end of the maze, rats push away each object to retrieve the reward and are given the opportunity to explore each object. On the test sesion they are given a choice (“Test”) of one object from block 1, first encountered ∼40 min prior, or another object from block 2, encountered ∼10 min prior. Rats with MTT lesions are significantly impaired when required to discriminate between objects based on relative recency (Nelson and Vann, 2016). In object-in-place experiments (b), a sample phase consisting of one arrangement of four different objects (A, B, C and D), is followed, after a 15 min delay, by a choice phase in which objects B and C had switched positions. Both intramaze cues (i.e., cue cards) and extramaze cues are available. Rats with MTT lesions were significantly impaired in discriminating objects in a novel position (B and C) from those in a familiar position (A and D) (Nelson and Vann, 2014). In the both experiments, preferential exploration of the ‘novel’ object (i.e. less recent or displaced objects) was expressed as a discrimination ratio calculated as subtracting the time spent exploring the familiar from the novel item divided by the total time exploring both objects.

Fig. 3

Physiological consequences of mammillothalamic tract (MTT) or mammillary body (MB) lesions. a, MTT lesions result in an attenuation of theta frequency in the CA1 subfield of the hippocampal formation and the retrosplenial cortex, the product of reduced ascending phase duration (trough-to-peak) of the theta cycle (b); c, lesions of MB (*and the supramammillary nucleus) reduce the frequency of hippocampal theta neuron entrainment by approximately 1 Hz; d, spectral coherence of hippocampal-retrospenial theta is increased in MTT lesioned animals, while theta-(high) gamma phase amplitude coupling in both regions is enhanced (e); f, Hippocampal place fields appear superficially intact following either MTT or MB lesions.

Fig. 4

A possible route through which the medial mammillary bodies (MBs) and their projections to the anterior thalamic nuclei might influence contextual representations in the hippocampal formation. a, As well as head direction cells, anteroventral (AV) and anteromedial (AM) thalamic nuclei contain a high proportion of theta entrained neurons, a proportion of which encode direction through through the frequency of theta bursting (Welday et al., 2011). The medial MBs also house a high proportion of theta entrained neurons as well as those that are correlated with running speed, and angular head velocity. If it is the case that AM/AV activity is driven by the MBs, ascending MB activity may influence parahippocampal periodic tuning through modulation of thalamic directionally/velocity controlled oscillators; activity which is critical to oscillatory interference models of entorhinal (EC) grid cell periodicity (b; see Winter et al., 2015); Direct (AM-EC) and indirect (AV-subiculum-EC) thalamic influence over the EC may in turn modulate theta frequency/cycle asymmetry (Dillingham et al., 2019) and the related fast gamma low gamma ratio (which are dominant in the descending and ascending phase of the theta cycle, respectively) in CA1. The fast gamma (EC-CA1 derived), slow gamma (CA3-CA1 derived) ratio is thought to reflect a variable focus on prospective (future action) planning (fast gamma dominant) vs. current position encoding (slow gamma dominant).