Biology subjects

Kaffman, A.

Publications and source records attributed to Kaffman, A..

3 recordsLinked to original sources

bioRxiv2024

Transient Impairment in Microglial Function Causes Sex-Specific Deficits in Synaptic and Hippocampal Function in Mice Exposed to Early Adversity

Abnormal development and function of the hippocampus are two of the most consistent findings in humans and rodents exposed to early life adversity, with males often being more affected than females. Using the limited bedding (LB) paradigm as a rodent model of early life adversity, we found that male adolescent mice that had been exposed to LB exhibit significant deficits in contextual fear conditioning and synaptic connectivity in the hippocampus, which are not observed in females. This is linked to altered developmental refinement of connectivity, with LB severely impairing microglial-mediated synaptic pruning in the hippocampus of male and female pups on postnatal day 17 (P17), but not in adolescent P33 mice when levels of synaptic engulfment by microglia are substantially lower. Since the hippocampus undergoes intense synaptic pruning during the second and third weeks of life, we investigated whether microglia are required for the synaptic and behavioral aberrations observed in adolescent LB mice. Indeed, transient ablation of microglia from P13-21, in normally developing mice caused sex-specific behavioral and synaptic abnormalities similar to those observed in adolescent LB mice. Furthermore, chemogenetic activation of microglia during the same period reversed the microglial-mediated phagocytic deficits at P17 and restored normal contextual fear conditioning and synaptic connectivity in adolescent LB male mice. Our data support an additional contribution of astrocytes in the sex-specific effects of LB, with increased expression of the membrane receptor MEGF10 and enhanced synaptic engulfment in hippocampal astrocytes of 17-day-old LB females, but not in LB male littermates. This finding suggests a potential compensatory mechanism that may explain the relative resilience of LB females. Collectively, these studies highlight a novel role for glial cells in mediating sex-specific hippocampal deficits in a mouse model of early-life adversity.

neuroscience↗

bioRxiv2023

Early Deprivation Impairs Perforant Pathway Connectivity and Contextual Memory in Adolescent Male Mice

Early-life adversity causes reduced hippocampal volume and abnormal hippocampal connectivity and function, with evidence indicating more prominent deficits in males compared to females. Reelin-positive projections from the lateral entorhinal cortex (LEC) to the dorsal hippocampus are essential for encoding contextual and semantic memories in diverse mammalian species, including humans and rodents. However, the impact of early-life adversity on these projections and their contribution to hippocampal-dependent deficits have not been reported. Using a modified limited bedding (LB) mouse model of early adversity that extends the impoverished conditions from birth to postnatal day 25 (P25), we found severe impairment in contextual fear conditioning for adolescent LB male but not LB female mice. Using retrograde tracing, we found that the number of reeling-positive projections from the LEC to the dorsal hippocampus is significantly reduced in LB males but not LB females. Further, the number of projections was highly correlated with deficits in contextual memory and hypomyelination in perforant pathway terminals located in the dorsal hippocampus. Ex vivo high-resolution diffusion magnetic resonance imaging confirmed reduced structural connectivity between the entorhinal cortex and the dorsal hippocampus and revealed extensive cortical atrophy that resembled abnormalities reported in children exposed to severe deprivation. Given the essential role that reelin-positive projections play in contextual memory, these findings suggest a novel mechanism to explain the pronounced contextual memory deficits seen in LB males.

neuroscience↗

bioRxiv2022

Early adversity changes the economic conditions of structural brain network organisation

Early adversity can change educational, cognitive, and mental health outcomes. However, the neural processes through which early adversity exerts these effects remain largely unknown. We used generative network modelling of the mouse connectome to test whether unpredictable postnatal stress shifts the constraints that govern the formation of the structural connectome. A model that trades off the wiring cost of long-distance connections with topological homophily (i.e. links between regions with shared neighbours) generated simulations that replicate the organisation of the rodent connectome. The imposition of early life adversity significantly shifted the best-performing parameter combinations toward zero, heightening the stochastic nature of the generative process. Put simply, unpredictable postnatal stress changes the economic constraints that shape network formation, introducing greater randomness into the structural development of the brain. While this change may constrain the development of cognitive abilities, it could also reflect an adaptive mechanism. In other words, neural development could harness heightened stochasticity to make networks more robust to perturbation, thereby facilitating effective responses to future threats and challenges. Significance statementChildren who experience adversity early in life - such as chronic poverty or abuse - show numerous neural differences that are linked to poorer cognition and mental health later in life. To effectively mitigate the burden of adversity, it is critical to identify how these differences arise. In this paper, we use computational modelling to test whether growing up in an impoverished and unpredictable environment changes the development of structural connections in the mouse brain. We found that early adversity appears to introduce more stochasticity in the formation of neural architecture. Our findings point to a potential mechanism for how early adversity could change the course of child development.

neuroscience↗