Benedetta Leuner

Structural Plasticity and Hippocampal Function

The hippocampus is a region of the mammalian brain that shows an impressive capacity for structural reorganization. Preexisting neural circuits undergo modifications in dendritic complexity and synapse number, and entirely novel neural connections are formed through the process of neurogenesis. These types of structural change were once thought to be restricted to development. However, it is now generally accepted that the hippocampus remains structurally plastic throughout life. This article reviews structural plasticity in the hippocampus over the lifespan, including how it is investigated experimentally. The modulation of structural plasticity by various experiential factors as well as the possible role it may have in hippocampal functions such as learning and memory, anxiety, and stress regulation are also considered. Although significant progress has been made in many of these areas, we highlight some of the outstanding issues that remain.

Diminished adult neurogenesis in the marmoset brain precedes old age.

With aging there is a decline in the number of newly generated neurons in the dentate gyrus of the hippocampus. In rodents and tree shrews, this age-related decrease in neurogenesis is evident long before the animals become aged. No previous studies have investigated whether primates exhibit a similar decline in hippocampal neurogenesis with aging. To investigate this possibility, young to middle aged adult common marmosets (Callithrix jacchus) were injected with BrdU and perfused 3 weeks later. The number of newly generated cells in the subgranular zone/granule cell layer of the dentate gyrus was significantly lower in older animals and decreased linearly with age. A similar age-related decline in new cells was observed in the subventricular zone but not in the hilar region of the dentate gyrus. These data demonstrate that a substantial decrease in neurogenesis occurs before the onset of old age in the adult marmoset brain, suggesting the possibility that similar alterations occur in the human brain.

Stress, anxiety, and dendritic spines: what are the connections?

Stressful life events, especially those that induce fear, can produce a state of anxiety that is useful for avoiding similar fearful and potentially dangerous situations in the future. However, they can also lead to exaggerated states, which over time can produce mental illness. These changing states of readiness versus illness are thought to be regulated, at least in part, by alterations in dendritic and synaptic structure within brain regions known to be involved in anxiety. These regions include the amygdala, hippocampus, and prefrontal cortex. In this article, we review the reciprocal relationships between the expression of stress- and anxiety-related behaviors and stress-induced morphological plasticity as detected by changes in dendrites and spines in these three brain regions. We begin by highlighting the acute and chronic effects of stress on synaptic morphology in each area and describe some of the putative mechanisms that have been implicated in these effects. We then discuss the functional consequences of stress-induced structural plasticity focusing on synaptic plasticity as well as cognitive and emotional behaviors. Finally, we consider how these structural changes may contribute to adaptive behaviors as well as maladaptive responses associated with anxiety.

Oxytocin stimulates adult neurogenesis even under conditions of stress and elevated glucocorticoids

Oxytocin has been linked to social behavior, including social recognition, pair bonding and parenting, but its potential role in promoting neuronal growth has not been investigated. We show here that oxytocin, but not vasopressin, stimulates both cell proliferation and adult neurogenesis in the hippocampus of rats. Oxytocin is also capable of stimulating adult neurogenesis in rats subjected to glucocorticoid administration or cold water swim stress. These findings suggest that oxytocin stimulates neuronal growth and may protect against the suppressive effects of stress hormones on hippocampal plasticity.

New spines, new memories

For more than a century dendritic spines have been a source of fascination and speculation. The long-held belief that these anatomical structures are involved in learning and memory are addressed. Specifically, two lines of evidence that support this claim are reviewed. In the first, we review evidence that experimental manipulations that affect dendritic spine number in the hippocampus also affect learning processes of various sorts. In the second, we review evidence that learning itself affects the presence of dendritic spines in the hippocampus. Based on these observations, we propose that the presence of spines enhances synaptic efficacy and thereby the excitability of the network involved in the learning process. With this scheme, learning is not dependent on changes in spine density but rather changes in the presence of dendritic spines provide anatomical support for the processing of novel information used in memory formation.

Sexual Experience Promotes Adult Neurogenesis in the Hippocampus Despite an Initial Elevation in Stress Hormones

Aversive stressful experiences are typically associated with increased anxiety and a predisposition to develop mood disorders. Negative stress also suppresses adult neurogenesis and restricts dendritic architecture in the hippocampus, a brain region associated with anxiety regulation. The effects of aversive stress on hippocampal structure and function have been linked to stress-induced elevations in glucocorticoids. Normalizing corticosterone levels prevents some of the deleterious consequences of stress, including increased anxiety and suppressed structural plasticity in the hippocampus. Here we examined whether a rewarding stressor, namely sexual experience, also adversely affects hippocampal structure and function in adult rats. Adult male rats were exposed to a sexually-receptive female once (acute) or once daily for 14 consecutive days (chronic) and levels of circulating glucocorticoids were measured. Separate cohorts of sexually experienced rats were injected with the thymidine analog bromodeoxyuridine in order to measure cell proliferation and neurogenesis in the hippocampus. In addition, brains were processed using Golgi impregnation to assess the effects of sexual experience on dendritic spines and dendritic complexity in the hippocampus. Finally, to evaluate whether sexual experience alters hippocampal function, rats were tested on two tests of anxiety-like behavior: novelty suppressed feeding and the elevated plus maze. We found that acute sexual experience increased circulating corticosterone levels and the number of new neurons in the hippocampus. Chronic sexual experience no longer produced an increase in corticosterone levels but continued to promote adult neurogenesis and stimulate the growth of dendritic spines and dendritic architecture. Chronic sexual experience also reduced anxiety-like behavior. These findings suggest that a rewarding experience not only buffers against the deleterious actions of early elevated glucocorticoids but actually promotes neuronal growth and reduces anxiety.

High levels of estrogen enhance associative memory formation in ovariectomized females

The ovarian hormone estrogen is presumed to modulate processes of learning and memory in adulthood. In this study, we examined the effects of short-term estrogen replacement on associative memory formation. Adult ovariectomized female rats received two injections of estradiol (10, 20 or 40 microg) 24 h apart and were trained 4 h following each injection on the hippocampal-dependent task of trace eyeblink conditioning. Only the highest dose of estrogen, which produced plasma estradiol levels >250 pg/ml, enhanced conditioned responding. One day after the last injection, estrogen treated rats continued to exhibit elevated levels of conditioning and extinguished responding when the conditioned stimulus was no longer presented. Exposure to estrogen did not alter pain sensitivity or activity levels, but did greatly increase uterine weight. These results provide additional support to the view that that ovarian steroids are beneficial to the performance of certain forms of learning and memory tasks, albeit at supraphysiological doses. They are discussed with reference to hormone replacement and its effects on cognitive processes.

The opposite effects of stress on dendritic spines in male vs. female rats are NMDA receptor‐dependent

Dendritic spines in the hippocampus are sources of synaptic contact that may be involved in processes of learning and memory [Moser (1999) Cell. Mol. Life Sci., 55, 593–600]. These structures are sensitive to sex differences as females in proestrus possess a greater density than males and females in other stages of the estrous cycle [Woolley et al.. (1990) J. Neurosci., 10, 4035–4039]. Moreover, exposure to an acute stressful event increases spine density in the male hippocampus but decreases spine density in the female hippocampus [Shors et al.. (2001) J. Neurosci., 21, 6292–6297]. Here we demonstrate that antagonism of N‐methyl‐d‐aspartate (NMDA) receptors prevents the increase in spine density as females transition from diestrus 2 to proestrus, when estrogen levels are rising. Antagonism of NMDA receptors during exposure to the stressful event also prevented the changes in spine density in males and females, despite differences in the direction of these effects. Thus, the stress‐induced increase in spine density was prevented in the male hippocampus as was the stress‐induced decrease in spine density in the female hippocampus. NMDA receptor antagonism during exposure to the stressful event did not alter corticosterone levels or the corticosterone response to stress. These data suggest that both increases and decreases in spine density can be dependent on NMDA receptor activation.

Males and Females Respond Differently to Controllability and Antidepressant Treatment

BACKGROUND Women are much more likely to suffer from stress-related mental illness than men; yet few, if any, animal models for such sex differences exist. Previously, we reported that exposure to an acute stressor enhances learning in male rats yet severely impairs learning in female rats. Here, we tested whether these opposite effects in males versus females could be prevented by establishing control over the stressor or by antidepressant treatment. METHODS Learning was assessed using the hippocampal-dependent task of trace eyeblink conditioning. In the first experiment, groups of male and female rats were exposed to controllable or uncontrollable stress and trained. In a second experiment, they were exposed to an uncontrollable stressor after chronic treatment with the antidepressant fluoxetine (Prozac). In a final experiment, females were exposed to uncontrollable stress after acute treatment with fluoxetine. RESULTS Establishing control over the stressful experience eliminated the detrimental effect of stress on learning in females as well as the enhancing effect of stress in males. Moreover, chronic but not acute treatment with fluoxetine prevented the learning deficit in females after exposure to stress. Treatment with fluoxetine did not alter the male response to stress. CONCLUSIONS These data indicate that males and females not only respond in opposite directions to the same stressful event but also respond differently to controllability and antidepressant treatments.

Parenting and plasticity

As any new parent knows, having a baby provides opportunities for enrichment, learning and stress - experiences known to change the adult brain. Yet surprisingly little is known about the effects of maternal experience, and even less about the effects of paternal experience, on neural circuitry not directly involved in parenting. Here we discuss how caregiving and the accompanying experiential and hormonal changes influence the hippocampus and prefrontal cortex, brain regions involved in cognition and mood regulation. A better understanding of how parenting impacts the brain is likely to help in devising strategies for treating parental depression, a condition that can have serious cognitive and mental health consequences for children.