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    • Our goal here was to develop a mouse model

    2018-11-14

    Our goal here was to develop a mouse model of effects of early life adversity on executive function with a focus on the subdomain of cognitive flexibility (also called updating in the RDoc system). Additionally, we sought to investigate how early life stress might contribute to the development of addiction-related behaviors by assessing ethanol consumption using an intermittent access “drinking in the dark” paradigm that leads to binge drinking episodes in mice (Rhodes et al., 2005; Thiele and Navarro, 2014). We choose to focus on mice to enable use of the wealth of tools for the study of neural circuits that are currently most developed in this species. There is a large body of work that has used rats as a model system to study the effects of early adverse experience on anxiety and fear behavior and also, to a lesser extent, cognitive function. Many of these models involve disruptions of the infant-mother relationship, which is thought to be one of the most important relationships in early life (Levine, 1962; Bowlby, 1982). Some studies have focused on comparing the offspring of mothers that provide low versus high levels of maternal care (Liu et al., 1997), while others have manipulated the amount of bedding to induce maternal stress and erratic behavior (Gilles et al., 1996; Ivy et al., 2008) or employed more invasive separation paradigms which remove pups from their mother during the early postnatal PyBOP cost (Plotsky and Meaney, 1993; Francis et al., 2002). The most invasive separation studies have used artificial rearing with no dam care at all (Lovic and Fleming, 2004). Rat pups that have experienced low care levels or maternal separation (MS) have been shown by a wealth of studies to exhibit altered stress reactivity and anxiety behavior (Liu et al., 1997; Huot et al., 2002; Ladd et al., 2004; Lippmann et al., 2007; Aisa et al., 2007; Pryce and Feldon, 2003; Gilles et al., 1996; Dalle Molle et al., 2012). A small but growing body of work has found evidence of cognitive changes in rats following early adverse experience. Adult rats that were artificially-reared (with no dam contact) have been shown to exhibit impairments in tests of cognitive flexibility in a 2-choice attentional set shifting paradigm (ASST) in which rodents learn to dig for cereal reward in scented or textured material and the rewarded contingency is reversed or the rewarded dimension is shifted (Lovic and Fleming, 2004). Impairments in 2-choice reversal in this same digging based task have also been found in adult rats that underwent 3h of maternal separation during the first two weeks of life (Baudin et al., 2012). Working memory and flexibility in spatial tasks has also been found to be altered in adolescent and adult rats following early maternal separation (Brenhouse and Andersen, 2011; but see Wang et al., 2015). Notably, there is less evidence of a maternal separation effect on cognitive flexibility in mice, a species in which we have greater access to the study of specific circuits. Furthermore, past studies in mice have found inconsistent results which call into question the reliability of the rodent model. One study found the effects of maternal separation on cognitive function was strain-dependent (Mehta and Schmauss, 2011). The Balb/c strain showed spatial working memory and set-shifting deficits in adulthood following maternal separation, while the adult C57Bl/6 strain showed no impairments across multiple cognitive domains. Importantly, this mouse study found no deficit in reversal learning in either strain. In contrast, other studies have found adult spatial learning impairments and working memory impairments, including deficits in spatial reversal in both C57Bl/6J (Fabricius et al., 2008) and Balb/cJ strain (Wang et al., 2011), and Y maze spontaneous alternation and temporal order memory in the C57Bl6 strain (Yang et al., 2015). Two of these positive findings however focus on spatial tasks dependent on the hippocampus rather than odor or texture based digging tasks that have been found to be dependent on the integrity of the frontal cortex of rodents (Birrell and Brown, 2000; Garner et al., 2006; Bissonette et al., 2008; Kim and Ragozzino, 2005; McAlonan and Brown, 2003).