CD8+ T cells are essential for the effects of enriched environment on hippocampus-dependent behavior, hippocampal neurogenesis and synaptic plasticity

Abstract

Enriched environment (EE) induces plasticity changes in the brain. Recently, CD4 T cells have been shown to be involved in brain plasticity processes. Here, we show that CD8 T cells are required for EE-induced brain plasticity in mice, as revealed by measurements of hippocampal volume, neurogenesis in the DG of the hippocampus, spinogenesis and glutamatergic synaptic function in the CA of the hippocampus. As a consequence, EE-induced behavioral benefits depend, at least in part, on CD8 T cells. In addition, we show that spleen CD8 T cells from mice housed in standard environment (SE) and EE have different properties in terms of 1) TNFα release after in vitro CD3/CD28 or PMA/Iono stimulation 2) in vitro proliferation properties 3) CD8 CD44 CD62L and CD62L T cells repartition 4) transcriptomic signature as revealed by RNA sequencing. CD8 T cells purified from the choroid plexus of SE and EE mice also exhibit different transcriptomic profiles as highlighted by single-cell mRNA sequencing. We show that CD8 T cells are essential mediators of beneficial EE effects on brain plasticity and cognition. Additionally, we propose that EE differentially primes CD8 T cells leading to behavioral improvement.

Influenza vaccination in early Alzheimer’s disease rescues amyloidosis and ameliorates cognitive deficits in APP/PS1 mice by inhibiting regulatory T cells

“…Further analysis indicated that the cytokines with different changes between the brain and serum are not completely consistent. Similarly, Zarif et al [55] demonstrated that T lymphocytes purified from the spleen and choroid plexus showed different mRNA transcriptomic profiles as reflected by single-cell RNA seq analyses. The above studies suggest distinguished immune cytokine profiles between the periphery and the brain.…”

Species differences in immune‐mediated CNS tissue injury and repair: A (neuro)inflammatory topic

“…For the adaptive immune system, both CD4 and CD8 T cells are implicated in influencing networks that underlie learning capacity (Ziv et al, 2006). Zarif et al demonstrated a role for CD8 T cells in learning through the regulation of hippocampal neurogenesis and synaptic plasticity (Zarif et al, 2018). Expression of MHC molecules in the CNS is also required for normal brain development (Bilbo & Schwarz, 2012;Lee et al, 2014).…”

Diversified Learning Environment Alleviates Learning Impairment Caused by Contextual Stress

“…Enriched environments are critical to the nervous system of juvenile and adult animals; they are likely to help reverse cognitive and emotional disorders. For mammals, the environment where they grow up noticeably impacted their negative emotional and neuronal development [33][34][35]. As revealed from the results here, for adult rats, simply increasing the diversity of training environments could effectively elevate the learning efficiency of animals without the need to enrich breeding environments.…”

“…Previous studies have shown that strengthened synaptic connection was found in hippocampus [35]and cortex [33]of animals housed in enriched environments and could be the neural mechanism responsible for the enhanced learning performance. Moreover, activation of prefrontal cortex in rats could enhance active avoidance performance and reduce freezing behavior to neutral conditioned stimuli by inhibiting neuron activities in amygdala [26].…”