2026 ECNP Congress

PS03-3010

Cognitive training under altitude-like hypoxia improves cognition in mice: results from the ALTIBRAIN preclinical trials

Ioanna Giannakou — A. Berezovskaia, D. Viktoria, E. Dere, H. Ehrenreich, G. Wörtwein, K. Miskowiak · Psychiatric Centre Copenhagen- Frederiksberg Hospital, NEAD Centre, Copenhagen, Denmark

2026 ECNP Congress

Cognitive impairment, a core symptom experienced by patients with neuropsychiatric disorders, is strongly linked to disrupted neuroplasticity [1]. Recent evidence points to hypoxia as a potential mechanism for promoting neuronal differentiation and neuroplasticity due to erythropoietin (EPO) production [2, 3]. In parallel, motor-cognitive challenge induces neuronal hypoxia, which can amplify these benefits [4]. However, it remains an open question whether hypoxia exposure and cognitive training can act on neuroplasticity together and produce greater pro-cognitive benefits than either modality alone. Therefore, this study aims to assess the synergistic effects of hypoxia and cognitive training ion cognitive functioning and EPO-dependent neuroplasticity.

Sixty-four female C57BL/6NCrl mice were randomly allocated to one of four conditions: 1. hypoxia with cognitive training, 2. normoxia with cognitive training, 3. hypoxia without cognitive training and 4. normoxia without cognitive training (N = 16 per group). Hypoxia was induced with a normobaric system (~12% O₂) for 3.5 hours daily throughout 24 consecutive days. The IntelliCage automated system was used for cognitive training, assessing place learning (PL), episodic-like memory (ELM), working memory (WM), and past-oriented mental time travel (MTT). One week following the intervention, mice were tested in the Open Field Task (OFT) for 4 consecutive days, with a change in context between day 2 and 3, to examine within and between session habituation and dishabituation, a form of non-associative learning. Animals were sacrificed the following day and brains were processed for Golgi–Cox staining to assess dendritic spine density in CA1 pyramidal neurons, and immunohistochemistry to quantify the expression of markers associated with neurogenesis, neuronal differentiation, and angiogenesis (DCX, Tbr1, ZBTB20, Ctip2, VEGF) in hippocampal sections.

The IntelliR pipeline was used to evaluate performance in the IntelliCage apparatus. Mice in the hypoxic condition demonstrated superior cognition, indicated by higher cognitive indices during the first day of the ELM challenge (ELM1 acquisition: t(32)=.368, p<.05) and across multiple days of the WM challenge (WM1: W=228, p<.001; WM2: W=198, p<.05; WM3: t(32)=4.975, p<.001), as well as increased learning rates across most challenges. Performance in the MTT challenge did not differ between groups. A linear mixed-effects model examining the effect of hypoxia and IntelliCage environment on distance traveled in the OFT revealed significant main effects of day (F(3,180)=26.88, p<.001), hypoxia (F(1,60)=7.04, p=.010) and IntelliCage environment (F(1,60)=41.11, p<.001), with animals in the IntelliCage environment and the hypoxic group displaying higher activity than the corresponding control group. A linear mixed model on habituation scores across consecutive OFT sessions demonstrated a significant interaction between day and hypoxia condition (F(2,180)=13.54, p<.001), as mice in the hypoxic group showed increased dishabituation between days 2 and 3, and enhanced habituation between days 3 and 4. Analysis of Golgi- and immunofluorescence-stained neurons is currently ongoing.

Our findings extend the results of the ALTIBRAIN clinical trials [5], providing valuable mechanistic understanding of hypoxia-enhanced cognitive improvement. The outcomes of our study align with and extend prior research demonstrating the pro-cognitive effects of hypoxia-induced neuroplasticity and offer valuable insight for the development of low-cost, scalable interventions for psychiatric populations with cognitive impairments.

References

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