Leptin promotes rapid dynamic changes in hippocampal dendritic morphology

O’Malley, Dervla; MacDonald, Neil; Mizielinska, Sarah; Connolly, Christopher N.; Irving, Andrew J.; Harvey, Jenni

doi:10.1016/j.mcn.2007.05.001

Cited by 158 publications

(135 citation statements)

References 69 publications

(102 reference statements)

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“…Our findings show that disruption of circadian timing results in changes in body temperature, increased obesity, and changes in the metabolic hormones, leptin and insulin, which themselves have effects on cognition and mood (36)(37)(38)(39)(40). The metabolic effects are accompanied by changes in mPFC neuronal morphology, with layer III neurons showing a reduction in overall complexity.…”

Section: Discussionmentioning

confidence: 75%

Disruption of circadian clocks has ramifications for metabolism, brain, and behavior

Karatsoreos

Bhagat

Bloss

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

487

380

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Circadian (daily) rhythms are present in almost all plants and animals. In mammals, a brain clock located in the hypothalamic suprachiasmatic nucleus maintains synchrony between environmental light/ dark cycles and physiology and behavior. Over the past 100 y, especially with the advent of electric lighting, modern society has resulted in a round-the-clock lifestyle, in which natural connections between rest/activity cycles and environmental light/dark cycles have been degraded or even broken. Instances in which rapid changes to sleep patterns are necessary, such as transmeridian air travel, demonstrate negative effects of acute circadian disruption on physiology and behavior. However, the ramifications of chronic disruption of the circadian clock for mental and physical health are not yet fully understood. By housing mice in 20-h light/dark cycles, incongruous with their endogenous ∼24-h circadian period, we were able to model the effects of chronic circadian disruption noninvasively. Housing in these conditions results in accelerated weight gain and obesity, as well as changes in metabolic hormones. In the brain, circadian-disrupted mice exhibit a loss of dendritic length and decreased complexity of neurons in the prelimbic prefrontal cortex, a brain region important in executive function and emotional control. Disrupted animals show decreases in cognitive flexibility and changes in emotionality consistent with the changes seen in neural architecture. How our findings translate to humans living and working in chronic circadian disruption is unknown, but we believe that this model can provide a foundation to understand how environmental disruption of circadian rhythms impacts the brain, behavior, and physiology.cognitive function | neuronal remodeling | structural plasticity | biological clock C ircadian (daily) rhythms in physiology and behavior are phylogenetically ancient and are present in almost all plants and animals (1). In mammals, these rhythms are generated by a master circadian clock in the suprachiasmatic nucleus (SCN) of the hypothalamus, which in turn synchronizes peripheral oscillators throughout the brain and body in almost all cell types and organ systems (2). Though circadian rhythms are phylogenetically ancient, modern industrialized society and the ubiquity of electric lighting has resulted in a fundamental alteration in the relationship between an individual's endogenous circadian rhythmicity and the external environment. The ramifications of this desynchronization for mental and physical health are not fully understood, although numerous lines of evidence are emerging that link defects in circadian timing with negative health outcomes (2, 3). Animal models have shown that chronic circadian disruption can alter mortality rates in tau mutant hamsters (4) and in aged mice (5). The current obesity epidemic in Western societies has also occurred hand-inhand with a gradual decrease in sleep time and sleep quality (6), and although largely correlative, a potential causal link is plausible. Indivi...

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Section: Discussionmentioning

confidence: 75%

Disruption of circadian clocks has ramifications for metabolism, brain, and behavior

Karatsoreos

Bhagat

Bloss

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

487

380

View full text Add to dashboard Cite

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“…as well as synaptic plasticity, dendritic spines/synapses and adult neurogenesis in the hippocampus (40)(41)(42). The cognitive-and plasticity-enhancing characteristics of leptin may thus be capable, at least during a short time frame, of preventing hippocampal dysfunction in the face of lower glucocorticoid signaling.…”

Section: Discussionmentioning

confidence: 99%

Obesity diminishes synaptic markers, alters microglial morphology, and impairs cognitive function

Bocarsly

Fasolino

Kane

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

210

151

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Obesity is a major public health problem affecting overall physical and emotional well-being. Despite compelling data suggesting an association between obesity and cognitive dysfunction, this phenomenon has received relatively little attention. Neuroimaging studies in obese humans report reduced size of brain regions involved in cognition, but few studies have investigated the cellular processes underlying cognitive decline in obesity or the influence of obesity on cognition in the absence of obesity-related illnesses. Here, a rat model of diet-induced obesity was used to explore changes in brain regions important for cognition. Obese rats showed deficits on cognitive tasks requiring the prefrontal and perirhinal cortex. Cognitive deficits were accompanied by decreased dendritic spine density and synaptic marker expression in both brain regions. Microglial morphology was also changed in the prefrontal cortex. Detrimental changes in the prefrontal cortex and perirhinal cortex occurred before metabolic syndrome or diabetes, suggesting that these brain regions may be particularly vulnerable to early stage obesity.O besity is a growing public health concern, affecting more than one-third of the United States adult population (1). Obesity increases the incidence of diabetes, vascular disease, and mental illness, all of which reduce quality of life and place a heavy financial burden on patients and society. Less recognized consequences of obesity are its deleterious effects on cognitive function. Individual cognitive performance, both rudimentary and scholastic, declines with increases in body mass and energy consumption (2-5). These deficits can be observed throughout life, from childhood to late adulthood. Obesity is also associated with an increased incidence of mild cognitive impairment and dementia in the elderly (6).Some evidence suggests that obese individuals have decreased overall brain volume (7), with further studies indicating more specific reductions in the volume of brain regions important for cognition, including the hippocampus, prefrontal cortex (PFC), and anterior cingulate (5,8,9). Few studies, however, have investigated the cellular and biochemical mechanisms that might underlie obesityinduced changes in brain volume and cognitive function.Although clinical studies strongly suggest that obesity produces cognitive impairment and brain atrophy, it is difficult to determine whether these changes arise from obesity itself or from conditions often associated with obesity, like metabolic syndrome, diabetes, and vascular disease. Such conditions, even in the absence of obesity, have been linked to cognitive dysfunction and decreases in brain volume (10-13). Little research has been done exploring the effects of obesity on brain structure and cognition in obese, but otherwise healthy, individuals. To investigate whether obesity in the absence of obvious illness alters brain structure and function, we used a rat model of dietinduced obesity to assess the PFC, the perirhinal cortex (PRC), and the hippocampus...

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“…Finally, leptin has been shown to be an essential factor for the formation of specific neuronal projection pathways within the hypothalamus [59]. A recent in vitro study demonstrated that leptin increases the motility and density of dendritic filopodia and the number of hippocampal synapses [60]. Key issues that remain to be addressed, however, are whether leptin is required for the formation of the limbic circuit and whether leptin's neurotrophic effects mediate its antidepressant effects.…”

Section: Neurotrophic Actions Of Leptinmentioning

confidence: 99%

The leptin hypothesis of depression: a potential link between mood disorders and obesity?

Lü

2007

Current Opinion in Pharmacology

259

198

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SummaryThe adipose-derived hormone leptin is well known for its function in the control of energy homeostasis. Recent studies suggest a novel role for this adipokine in the regulation of mood and emotion. Low levels of leptin have been found to be associated with depressive behaviors in rodents and humans. Pharmacological studies indicate that leptin has antidepressant-like efficacy. Both leptin insufficiency and leptin resistance may contribute to alterations of affective status. Identifying the key brain regions that mediate leptin's antidepressant activity and dissecting its intracellular signal transduction pathways may provide new insights into the pathogenesis of depression and facilitate the development of novel therapeutic strategies for the treatment of this illness.

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Leptin promotes rapid dynamic changes in hippocampal dendritic morphology

Cited by 158 publications

References 69 publications

Disruption of circadian clocks has ramifications for metabolism, brain, and behavior

Disruption of circadian clocks has ramifications for metabolism, brain, and behavior

Obesity diminishes synaptic markers, alters microglial morphology, and impairs cognitive function

The leptin hypothesis of depression: a potential link between mood disorders and obesity?

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