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

3D mapping reveals network-specific amyloid progression and subcortical susceptibility in mice

Alzheimer’s disease (AD) is a progressive, neurodegenerative dementia with no cure. Prominent hypotheses suggest accumulation of beta-amyloid (Aβ) contributes to neurodegeneration and memory loss, however identifying brain regions with early susceptibility to Aβ remains elusive. Using SWITCH to immunolabel intact brain, we created a spatiotemporal map of Aβ deposition in the 5XFAD mouse. We report that subcortical memory structures show primary susceptibility to Aβ and that aggregates develop in increasingly complex networks with age. The densest early Aβ occurs in the mammillary body, septum, and subiculum- core regions of the Papez memory circuit. Previously, early mammillary body dysfunction in AD had not been established. We also show that Aβ in the mammillary body correlates with neuronal hyper-excitability and that modulation using a pharmacogenetic approach reduces Aβ deposition. Our data demonstrate large-tissue volume processing techniques can enhance biological discovery and suggest that subcortical susceptibility may underlie early brain alterations in AD.

Dynamic Changes in the Localization of Neuronatin-Positive Cells during Neurogenesis in the Embryonic Rat Brain

Neuronatin (NNAT) was first identified as a gene selectively and abundantly expressed in the cytoplasm of the newborn mouse brain, and involved in neonatal neurogenesis. However, the particular roles of NNAT in the developing prenatal brain have not been identified, especially in mid to late stages. In this study, we performed immunohistochemical analyses of NNAT and SOX2 proteins, a nuclear transcription factor and neural stem/progenitor marker, in the rat brain on embryonic days 13.5, E16.5, and E20.5. NNAT signals were broadly observed across the developing brain on E13.5 and gradually more localized in later stages, eventually concentrated in the alar and basal parts of the terminal hypothalamus, the alar plate of prosomere 2 of the thalamus, and the choroid plexus in the lateral and fourth ventricles on E20.5. In particular, the mammillary body in the basal part of the terminal hypothalamus, a region with a high number of SOX2-positive cells, evidenced intense NNAT signals on E20.5. The intracellular localization of NNAT showed diverse profiles, suggesting that NNAT was involved in various cellular functions, such as cell differentiation and functional maintenance, during prenatal neurogenesis in the rat brain. Thus, the present observations suggested diverse and active roles of the NNAT protein in neurogenesis. Determining the function of this molecule may assist in the elucidation of the mechanisms involved in brain development.

Structural hypothalamic abnormalities in amyotrophic lateral sclerosis (ALS)

ALS is a disease that progressively affects the upper and lower motor neurons concomitantly. Early pronounced weight loss is a common symptom, which correlates with survival time. Our hypothesis is that this symptom originates from changes in the hypothalamus, which is essential in metabolic control. Therefore, the objective of this study was to determine if there are volumetric changes in the hypothalamus region, through the Multi-Atlas T1, in patients with ALS compared to a control group, and if there is correlation with clinical parameters.The mean ALSFRS score and disease duration were 32 and 3.8 years, respectively. ​In the volumetric analyses, there were no significant differences between patients and controls regarding Hypothalamus, Mammillary Body, Nucleus Accumbens , Anterior Basal Forebrain, and right-sided Posterior Basal Forebrain and Claustrum volumes. In contrast, we found left-sided Claustrum (p = 0.0002) and Posterior Basal Forebrain (p = 0.02) atrophy in the ALS group. There was no significant correlation between clinical parameters.Although there was no significant atrophy in the hypothalamus, nearby areas also involved in metabolic control were found abnormal in the patients. This reiterates the hypothesis that metabolic dysregulation is behind ALS-related cachexia.