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Dysregulation of metabolism and emotion is shared across these disorders and may be caused by hypothalamic pathology. Inclusions with TDP-43 are present in the hypothalamus in clinical ALS, as well as selective loss of hypothalamic neurons expressing the metabolism and emotion regulating neuropeptides hypocretin (orexin), melanin-concentrating hormone (MCH) and oxytocin. We aimed to investigate whether there is a casual link between the effects of TDP-43 in the hypothalamus and the development of neuropathology, as well as changes in metabolism and behavior. We generated an adeno-associated viral (AAV) vector expressing human TDP-43 under the neuronal-specific synapsin promoter, which was injected bilaterally into the hypothalamus of wild-type FVB\/N mice. TDP-43 overexpression resulted in hypothalamic pathology in a dose-dependent fashion replicating clinical pathology with hypothalamic atrophy and loss of hypocretin-, MCH- and oxytocin-expressing neurons. Nuclear and cytoplasmic inclusions of TDP-43 were found in the hypothalamus. Mice overexpressing TDP-43 in the hypothalamus developed metabolic dysregulation with hyperglycaemia independent of food intake. Additionally, mice overexpressing TDP-43 in the hypothalamus exhibited reduced motor activity and nesting ability, suggesting the development of an apathy-like phenotype. Taken together, AAV-vector mediated TDP-43 overexpression in the hypothalamus leads to neuropathology with the development of metabolic dysfunction and apathy-like behavior. These results indicate that TDP-43 can exert direct pathological effects in the hypothalamus, which may contribute to the development of the non-motor phenotype in TDP-43 proteinopathies.<\/jats:p>","DOI":"10.1186\/s40478-025-02018-8","type":"journal-article","created":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T05:36:35Z","timestamp":1748324195000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["TDP-43 overexpression in the hypothalamus drives neuropathology, dysregulates metabolism and impairs behavior in mice"],"prefix":"10.1186","volume":"13","author":[{"given":"Sofia","family":"Bergh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Casadei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanaz","family":"Gabery","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oskar","family":"Simonsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jo\u00e3o M. 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