Chronic interleukin-1β in the dorsal hippocampus impairs behavioural pattern separation

Highlights

• Chronic overexpression of hippocampal IL-1β impaired pattern separation.

• Chronic overexpression of IL-1β decreased hippocampal neurogenesis.

• Other hippocampal-dependent tasks were unaffected by overexpression of IL-1β.

• Disruption of adult neurogenesis by IL-1β may cause selective cognitive dysfunction.

Abstract

Understanding the long-term consequences of chronic inflammation in the hippocampus may help to develop therapeutic targets for the treatment of cognitive disorders related to stress, ageing and neurodegeneration. The hippocampus is particularly vulnerable to increases in the pro-inflammatory cytokine interleukin-1β (IL-1β), a mediator of neuroinflammation, with elevated levels implicated in the aetiology of neurodegenerative diseases such as Alzheimer’s and Parkinson’s, and in stress-related disorders such as depression. Acute increases in hippocampal IL-1β have been shown to impair cognition and reduce adult hippocampal neurogenesis, the birth of new neurons. However, the impact of prolonged increases in IL-1β, as evident in clinical conditions, on cognition has not been fully explored. Therefore, the present study utilized a lentiviral approach to induce long-term overexpression of IL-1β in the dorsal hippocampus of adult male Sprague Dawley rats and examine its impact on cognition. Following three weeks of viral integration, pattern separation, a process involving hippocampal neurogenesis, was impaired in IL-1β-treated rats in both object-location and touchscreen operant paradigms. This was coupled with a decrease in the number and neurite complexity of immature neurons in the hippocampus. Conversely, tasks involving the hippocampus, but not sensitive to disruption of hippocampal neurogenesis, including spontaneous alternation, novel object and location recognition were unaffected. Touchscreen operant visual discrimination, a cognitive task involving the prefrontal cortex, was largely unaffected by IL-1β overexpression. In conclusion, these findings suggest that chronically elevated IL-1β in the hippocampus selectively impairs pattern separation. Inflammatory-mediated disruption of adult hippocampal neurogenesis may contribute to the cognitive decline associated with neurodegenerative and stress-related disorders.

Introduction

There is a growing consensus that the increasing impact of age- and stress-related inflammatory insults on daily living positions neuroinflammation as a significant protagonist of neurodegeneration and associated cognitive disorders (Amor et al., 2010, Ryan and Nolan, 2016). The hippocampus is particularly vulnerable to neuronal degeneration and the consequent cognitive dysfunction associated with ageing, neurodegenerative and psychiatric disorders (Bartsch and Wulff, 2015). The pro-inflammatory cytokine interleukin-1β (IL-1β), a major mediator of neuroinflammation, and its cognate receptor are expressed at high levels within the hippocampus (Ban et al., 1991, Parnet et al., 1994). While evidence indicates that IL-1β is required for hippocampal-dependent cognition under quiescent conditions, it is well established that IL-1β has a detrimental effect on memory processes under chronic inflammatory conditions such as those associated with neurodegenerative disorders (Goshen et al., 2007, Kohman and Rhodes, 2013, Lynch et al., 2010). Furthermore, acute IL-1β treatment inhibits long-term potentiation (LTP) in the hippocampus (Lynch, 2015), and impairs both spatial and contextual memory (Barrientos et al., 2002, Gibertini et al., 1995, Goshen et al., 2007). Acute IL-1β exposure also negatively impacts upon hippocampal neurogenesis, the birth of new neurons, both in vitro (Green and Nolan, 2012, Ryan et al., 2013, Zunszain et al., 2012) and in vivo (Goshen et al., 2008, McPherson et al., 2011). Together, these findings suggest that IL-1β may mediate inflammation-induced changes in cognition by affecting hippocampal-dependent processes associated with hippocampal neurogenesis (Hueston et al., 2017, O'Léime et al., 2017, Yirmiya and Goshen, 2011). However, the impact of prolonged increases in IL-1β on hippocampal neurogenesis-dependent cognitive function is yet to be fully explored.

Adult hippocampal neurogenesis has been shown to be necessary for cognitive tasks which require spatial memory and contextual memory and has also been implicated in anxiety and forgetting (Clelland et al., 2009, Frankland et al., 2013, Revest et al., 2009, Saxe et al., 2006, Snyder et al., 2005). An important aspect of learning and memory is the ability to encode newly formed memories in a discrete non-overlapping fashion so as to reduce interference between similarly encoded memories (Tulving and Markowitsch, 1998). The process of discriminating between similar contextual memories has been referred to as pattern separation and has been repeatedly associated with hippocampal neurogenesis (Aimone et al., 2011, Sahay et al., 2011). In recent years, novel tests have been developed to tease apart the relationship between hippocampal neurogenesis and cognitive function, including touchscreen-based tests. These allow for testing multiple types of cognitive tasks utilizing the same platform, and increase the translational power of preclinical research findings (Bekinschtein et al., 2013, Horner et al., 2013, Oomen et al., 2013).

As current evidence points to inflammation as a protagonist of both cognitive dysfunction and adult hippocampal neurogenesis, the hypothesis of the current study was that chronically elevated hippocampal IL-1β impairs location discrimination in both touchscreen-based and non-touchscreen behavioural paradigms through disruption of the development of new adult neurons. Understanding the basis of inflammatory-induced changes in hippocampal neurogenesis-associated cognition will provide us with valuable information on the functional importance of new neurons, and the potential use of adult neurogenesis for repair and regeneration of hippocampal function.