The causal involvement of the BDNF-TrkB pathway in dentate gyrus in early-life stress-induced cognitive deficits in male mice

Abstract

Cognitive dysfunction is a significant, untreated clinical need in patients with psychiatric disorders, for which preclinical studies are needed to understand the underlying mechanisms and to identify potential therapeutic targets. Early-life stress (ELS) leads to long-lasting deficits of hippocampus-dependent learning and memory in adult mice, which may be associated with the hypofunction of the brain-derived neurotrophic factor (BDNF) and its high-affinity receptor, tropomyosin receptor kinase B (TrkB). In this study, we carried out eight experiments using male mice to examine the causal involvement of the BDNF-TrkB pathway in dentate gyrus (DG) and the therapeutic effects of the TrkB agonist (7,8-DHF) in ELS-induced cognitive deficits. Adopting the limited nesting and bedding material paradigm, we first demonstrated that ELS impaired spatial memory, suppressed BDNF expression and neurogenesis in the DG in adult mice. Downregulating BDNF expression (conditional BDNF knockdown) or inhibition of the TrkB receptor (using its antagonist ANA-12) in the DG mimicked the cognitive deficits of ELS. Acute upregulation of BDNF (exogenous human recombinant BDNF microinjection) levels or activation of TrkB receptor (using its agonist, 7,8-DHF) in the DG restored ELS-induced spatial memory loss. Finally, acute and subchronic systemic administration of 7,8-DHF successfully restored spatial memory loss in stressed mice. Subchronic 7,8-DHF treatment also reversed ELS-induced neurogenesis reduction. Our findings highlight BDNF-TrkB system as the molecular target of ELS-induced spatial memory deficits and provide translational evidence for the intervention at this system in the treatment of cognitive deficits in stress-related psychiatric disorders, such as major depressive disorder.

Heterogenous effect of early adulthood stress on cognitive aging and synaptic function in the dentate gyrus

“…The serial micrographs were aligned using software program (Reconstruct 1 ). The granule cell density was estimated based on the "Physical dissector" principle (Sterio, 1984;Gundersen et al, 1988) at the dorsal limb of dentate gyrus. Pairs of images were compared in succession.…”

“…1 http://synapses.bu.edu/tools Dissector frames (100 μm × 40 μm) were randomly placed on the individual reference images (Figure 6A). If a cell sampled in 'reference' section was not seen in the 'look up' section, the cell was counted (Sterio, 1984, Gundersen et al, 1988. Granule cell density was calculated using the following formula: Nv = Total number of counted cells/Sum of Areas of disector frame × Section thickness (Sterio, 1984).…”

“…In aged rats, the cortical inputs to the dentate gyrus were substantially reduced compared to the subsequent intrinsic connection of CA3 and its outputs to CA1 ( Geinisman et al, 1992 ; Smith et al, 2000 ; Geinisman et al, 2004 ). Long-term stress exposure leads to a continuous suppression of neurogenesis and modification in the structure of the dentate gyrus ( Alves et al, 2018 ; Chenani et al, 2022 ; Segi-Nishida and Suzuki, 2022 ; Sun et al, 2023 ). Therefore, the DG might be a critical area for comprehending cognitive function changes in the aging process with exposure to early adulthood stress.…”

Engeletin alleviates depression‐like phenotype by increasing synaptic plasticity via the BDNF‐TrkB‐mTORC1 signalling pathway

“…8,9 Furthermore, stress-induced negative cellular functional and morphological alterations in the prefrontal cortex (PFC) are consistent with the levels of essential receptors and proteins associated with synaptic plasticity. 10,11 These studies indicate that BDNF signalling pathway stimulation and PFC synaptic plasticity are novel targets against depression. Dihydrokaempferol 3-O-a-L-rhamnoside, also called engeletin (Figure 1), is among the most abundant and markedly active components of Smilax glabra rhizomilax.…”

“…Antidepressants modulate the brain‐derived neurotrophic factor (BDNF) and induce antidepressant‐like influence in short‐term behavioural depression models 8,9 . Furthermore, stress‐induced negative cellular functional and morphological alterations in the prefrontal cortex (PFC) are consistent with the levels of essential receptors and proteins associated with synaptic plasticity 10,11 . These studies indicate that BDNF signalling pathway stimulation and PFC synaptic plasticity are novel targets against depression.…”