The Effect of General Anesthesia on the Hippocampus

By April 19, 2021Uncategorized

While general anesthesia (GA) can safely and reversibly induce unconsciousness, exposure to GA may, as has grown increasingly evident, give rise to cellular and structural changes throughout the brain and hippocampus, incurring both neurotoxic and neuroprotective effects (1). Some of these effects may be long-lasting and may translate into cognitive and behavioral deficits, given the key role of the hippocampus in memory and cognition, as well as the fact that postnatal hippocampal neurogenesis persists into adulthood (2). As such, the United States Food and Drug Administration issued in 2016 a precautionary communication on GA use in patients under 3 years of age (3).

The effects of GA span a range of intra- and intercellular scales. During a critical period of brain development, midazolam, a pre-anesthetic, not only increases the rate of formation of dendritic spines but also the stability of newly formed spines. These two mechanisms together lead to a sustained increase in dendritic spine densities forming fully functional synapses (4).

In general, general anesthesia may impair neuronal maturation and survival in the hippocampus, as well as neurogenesis. One study found that propofol, which can be used as an induction agent during general anesthesia, impairs the maturation and survival of adult-born hippocampal neurons (4), while another study highlighted a certain age sensitivity of cells to these impacts, as propofol induced a marked decrease in the survival and dendritic maturation of 17-day-old, but not 11-day-old, hippocampal neurons at the time of anesthesia (5). This cell age-dependent vulnerability of neurons to anesthetic toxicity has since been replicated (6). Impaired neurogenesis and cellular function have also been demonstrated to be drug- and sex-specific. One study found that isoflurane, specifically, induced hippocampal cell injury and cognitive impairments in adult rats (7), while another demonstrated that propofol produces short-lived impairments, while midazolam and dexmedetomidine alter cognition after a several-week delay through mechanisms associated with decreased neurogenesis (8). Behaviorally, GA administered to postnatal day 6 (P6) rhesus monkeys was found also to result in increased anxiety and emotional reactivity when they reached 6 months of age; this also impaired hippocampus-related learning tasks in adulthood (9).

At a molecular level, general anesthesia induces neuroinflammation – including in the hippocampus. Specifically, one research study showed the GA-activated canonical nuclear factor-κB pathway to be linked to increased isoflurane-induced hippocampal interleukin-1β levels and resultant cognitive deficits in aged rats (10), while another research team demonstrated hippocampal and extra-hippocampal dysfunction due to neuroinflammation following GA (11). These effects appear anesthetic-specific (12).

A range of additional intracellular effects have also been identified. First, the exposure of P7 rat pups to 6-hour anesthesia has been shown to induce aberrant mitochondrial morphology in neurons and a marked reduction in the number of mitochondrion-containing presynaptic terminals in the hippocampal subiculum (13,14). In addition, hippocampal tau protein phosphorylation has been linked to isoflurane-induced cognitive dysfunction in mice (15). Finally, at a cytoarchitectural level, one study found long-erm effects of single or multiple sevoflurane exposures on rat hippocampal ultrastructure (16).

General anesthesia has ostensibly different impacts on the hippocampus in anesthetic-, brain developmental stage-, and age-specific ways. Clearly, further laboratory work and clinical investigations are warranted to ensure the prevention of any lasting adverse effects on the human brain and hippocampal function in particular.


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