Kohman Lab

Research themes:

1. Sex differences in inflammation-induced deficits in learning/memory and hippocampal neurogenesis.

2. The physiological function of Toll-like-receptor-4 (TLR4) in learning and memory.

3. Development of chronic neuroinflammation in normal and pathological aging.

4. Identifying interventions (e.g., exercise, anti-inflammatory compounds) to regulate neuroinflammation.

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Select projects:

 

Sex-dependent effects of inflammation on cognitive function and adulthood hippocampal neurogenesis: A wealth of evidence has established that activation of the immune system impairs learning and memory. These deficits are attributed to microglia activation and the production of immune-related signaling molecules, such as proinflammatory cytokines. In agreement, our research has shown that stimulating an inflammatory response with the bacterial endotoxin lipopolysaccharide (LPS) disrupts associative and spatial learning (Kohman et al., 2010). Additionally, we have shown that immune activity influences neuronal differentiation of newly born cells in the adult hippocampus (Littlefield et al., 2015). However, these experiments were limited to males. Presently, my laboratory is actively working to extend these data to females. Our laboratory was the first to demonstrate that females are resilient to LPS-induced avoidance learning deficits, whereas males are susceptible. Moreover, this resiliency in females occurred at increasing LPS doses despite having comparable levels of neuroinflammation (Patel et al., 2023). Ongoing projects will determine whether females are protected from inflammation-induced disruption of hippocampal neurogenesis and investigate potential mechanisms of these sex differences.

 

Toll-like receptor-4 (TLR4) engagement in learning/memory: In a series of projects, we evaluated the physiological role of the immune receptor, TLR4, in cognitive function by using TLR4 knockout (TLR4-/-) mice and a TLR4 antagonist. Our findings demonstrated that TLR4 has differential effects on spatial memory across age and sex, as young TLR4-/- males and aged TLR4-/- females showed enhanced spatial learning and memory compared to wild-type (WT) mice (Potter et al., 2019). Interestingly, the administration of a TLR4 antagonist selectively enhanced spatial memory in young females, which may result from attenuating stress reactivity (Connolly et al., 2021). Collectively, these data demonstrate the sexually dimorphic effects of TLR4 inhibition on cognitive function. Moreover, the knockout and pharmacological data indicate that the developmental stage of TLR4 suppression impacts the function of TLR4. Ongoing research will extend the investigation to alternative cognitive processes and explore the underlying mechanisms.

 

Voluntary exercise as an intervention to regulate neuroinflammation: Our research focuses on the potential utility of voluntary exercise, in the form of wheel running, to attenuate the basal neuroinflammatory state that develops with aged. Our early results showed that voluntary wheel running attenuated the expression of several inflammation-related genes in aged mice (Kohman et al., 2011). In subsequent experiments, our findings showed sex-dependent changes in microglia activation following exercise. While aged microglia from both sexes had increased activation (i.e., CD68 and MHC II positive, as measured by flow cytometry) relative to young mice. In aged females, voluntary wheel running decreased the proportion of hippocampal microglia positive for CD68 and MHC II relative to controls. In contrast, exercise had the opposite effect in aged males (Kohman et al., 2013). A separate series of projects demonstrated that access to a running wheel influences microglia phenotype in the aged, as exercising increased the proportion of microglia that co-labeled with the neuroprotective molecules insulin-like growth factor (IGF-1) and brain derived neurotrophic factor (BDNF) (Kohman et al., 2012; Littlefield et al., 2015). Our recent study demonstrated that the ability of exercise to attenuate age-related neuroinflammation depends on the length of the exercise training (Connolly et al., 2022). Collectively, these data indicate that exercise dampens age-related neuroinflammation but that the response may differ as a function of training duration and sex. This warrants further investigation to inform decisions about using exercise therapy to reduce inflammation across the sexes.