A Cognitive Rehabilitation Paradigm Effective in Male Rats Lacks Efficacy in Female Rats

Abstract

Cognitive dysfunction, as a consequence of dementia, is a significant cause of morbidity lacking efficacious treatment. Females comprise at least half of this demographic but have been vastly underrepresented in preclinical studies. The current study addressed this gap by assessing the protective efficacy of physical exercise and cognitive activity on learning and memory outcomes in a rat model of vascular dementia. Forty ovariectomized Sprague-Dawley rats (B6 months old) were exposed to either a diet high in saturated fats and refined sugars or standard laboratory chow and underwent either chronic bilateral carotid occlusion or Sham surgery. Learning and memory abilities were evaluated using standard cognitive outcomes over the ensuing 6 months, followed by histologic analyses of hippocampal CA1 neurons. In Experiment 1, we confirmed hypoperfusion-induced cognitive dysfunction using a 2  2 (Surgery  Diet) experimental design, without alterations in hippocampal architecture. In Experiment 2, hypoperfused animals were either exposed to alternating days of physical (wheel running) and cognitive activity (modified Hebb-Williams maze) or sedentary housing. In contrast to males, this combination rehabilitation paradigm did not improve cognition or histopathologic outcomes in hypoperfused animals. These findings, highlighting differences between female and male animals, show the necessity of including both sexes in preclinical experimentation.

Promoting brain health through exercise and diet in older adults: a physiological perspective

“…Indeed, the brain responds to vascular insults by marshalling a wide array of self-protective mechanisms (Iadecola & Anrather, 2011) that stands in marked contrast to the single-target approach used to treat AD, stroke and other neurological disorders. Consequently, a series of studies (Langdon & Corbett, 2012;Langdon et al 2013Langdon et al , 2014 that combined a PA intervention with a CA intervention were conducted in rodents to determine if this combined approach was more effective in enhancing cognitive function than either intervention alone. In the first of these studies rats were exposed to running wheels (PA) for 2 h per day, 5 days a week or to different versions of a Hebb-Williams maze (CA) for an identical time period or the combination of PA and CA.…”

“…Whether the hippocampal CA1 hypertrophy represents a pathological state preceding cell death or instead an intrinsic repair response is not clear, but a similar form of CA1 hypertrophy was found in asymptomatic autopsy brains in the Nun study (Iacono et al 2009). Finally, a note of caution must be expressed because the PA-CA intervention used to enhance cognitive performance in young, intact male rats (Langdon et al 2013) and to blunt the cognitive impairments in a middle-aged, male rat model of VCI did not provide cognitive benefit in a cohort of ovariectomised, middle-aged female rats (Langdon et al 2014). The reasons why the cognitive rehabilitation paradigm was effective in male but not female rats is unclear but it may relate to reduced levels of BDNF as a result of ageing and ovariectomy (Langdon et al 2014).…”

“…) and to blunt the cognitive impairments in a middle‐aged, male rat model of VCI did not provide cognitive benefit in a cohort of ovariectomised, middle‐aged female rats (Langdon et al . ). The reasons why the cognitive rehabilitation paradigm was effective in male but not female rats is unclear but it may relate to reduced levels of BDNF as a result of ageing and ovariectomy (Langdon et al .…”

“…The reasons why the cognitive rehabilitation paradigm was effective in male but not female rats is unclear but it may relate to reduced levels of BDNF as a result of ageing and ovariectomy (Langdon et al . ). Thus a greater ‘dose’ of exercise may be required to achieve the same levels of BDNF and cognitive performance in female as in male rats, which is in agreement with the aforementioned findings of Pialoux et al .…”

“…Consequently, a series of studies (Langdon & Corbett, ; Langdon et al . , ) that combined a PA intervention with a CA intervention were conducted in rodents to determine if this combined approach was more effective in enhancing cognitive function than either intervention alone. In the first of these studies rats were exposed to running wheels (PA) for 2 h per day, 5 days a week or to different versions of a Hebb–Williams maze (CA) for an identical time period or the combination of PA and CA.…”