Neuroplasticity in the maternal hippocampus: Relation to cognition and effects of repeated stress.

This article is part of a Special Issue "Parental Care". It is becoming clear that the female brain has an inherent plasticity that is expressed during reproduction. The changes that occur benefit the offspring, which in turn secures the survival of the mother's genetic legacy. Thus, the onset of maternal motivation involves basic mechanisms from genetic expression profiles, to hormone release, to hormone-neuron interactions, all of which fundamentally change the neural architecture - and for a period of time that extends, interestingly, beyond the reproductive life of the female. Although multiple brain areas involved in maternal responses are discussed, this review focuses primarily on plasticity in the maternal hippocampus during pregnancy, the postpartum period and well into aging as it pertains to changes in cognition. In addition, the effects of prolonged and repeated stress on these dynamic responses are considered. The maternal brain is a marvel of directed change, extending into behaviors both obvious (infant-directed) and less obvious (predation, cognition). In sum, the far-reaching effects of reproduction on the female nervous system provide an opportunity to investigate neuroplasticity and behavioral flexibility in a natural mammalian model.

Reproductive experiential regulation of cognitive and emotional resilience.

Adaptation virtually defines survival. For mammals, arguably, no other developmental milestone is exemplified by--nor more reliant on--the sudden and dramatic behavioral alterations observed in the maternal female, which rapidly must undergo change in order to express a large suite of proper and effective maternal behaviors. As pregnancy progresses, as well as during lactation, when pup cues are rich and rampant, the female is literally transformed from an organism that actively avoided offspring-related signals, to one highly motivated by those same cues to build nests, be attracted to pups and to retrieve, group, groom, crouch-over, care for, and protect, the young. Ancillary responses such as reference memory, spatial learning, foraging (including predation), and boldness improve in mothers compared to virgins. Such modifications arise early and are persistent, with neural benefits that last well into senescence. Evolutionarily, such enhancements have likely reduced the maternal burdens associated with sheltering and feeding the vulnerable young; collectively, this strengthens the mother's/parent's reproductive fitness and that of the pups in which all this effort is invested. Of the many behaviors that change as a function of pending or concurrent maternity, therefore, what is the role of modifications to resilience, the ability to withstand the numerous, unpredictable, and threatening environmental events that the mother/parent must daily, indeed, multiply daily, face and thwart in order to bring the offspring from pups to fully functioning adults. We explore these questions, and their connections, here in a multi-disciplinary manner focused on the constellation of change that summates to fundamentally alter the female for the rest of her life. Behavior, brain, neurochemistry and genes are fundamentally changed as the substrate for reproduction unfolds and expresses its inherent plasticity.

Epigenetic changes brought about by perinatal stressors: a brief review of the literature.

INTRODUCTION: Numerous studies employing various animal models have found that perinatal stress, encountered in utero during sensitive developmental stages or shortly after birth, disrupts both sexual differentiation and sexual behavior in offspring. The biochemical, cellular, genetic and epigenetic events which are involved in the organismal response to perinatal stress are currently under investigation. METHODS, RESULTS AND DISCUSSION: In this review, the reader is introduced to perinatal stressors as a toxicological phenomenon, and several recently characterized epigenetic responses to said stressors are discussed.

Reproductive experience facilitates recovery from kainic acid-induced neural insult in female Long-Evans rats.

The hormones of pregnancy and lactation (e.g., estrogen, progesterone, and oxytocin) have been shown to modulate learning, memory, and the restructuring of brain areas not traditionally associated with maternal behavior. Given the impact of reproductive experience on plasticity of brain areas such as the hippocampus, kainic acid (KA) was used in the current study to induce hippocampal-specific neurotoxic insult in adult multiparous and virgin Long-Evans rats. In Experiment I, Fluoro-Jade B, an indicant of degenerating cells, revealed significant neuronal damage in KA-treated hippocampi at 16 h post-injection in both maternal and virgin rats. In Experiment II, maternal and virgin rats were assessed in spatial and novel object preference tasks to determine the effects of KA on subsequent behavioral and cognitive responses. Twenty-four hours post injection, saline maternal animals exhibited superior memory in a spatial task. Further, maternal saline-injected rats were more similar to maternal KA-injected rats than both the virgin groups. Forty-eight hours following the KA or saline injection, compared to virgins, maternal animals demonstrated enhanced memory in the novel object memory test, regardless of type of injection. Further, neurobiological assessments in Experiment II indicated that virgin KA exposed rats had significantly more glial fibrillary acidic protein (GFAP)-immunoreactivity in the hippocampus, suggesting that they were in an earlier stage of neural recovery compared to maternal animals or, alternatively, may have exhibited more trauma than maternal animals. Together, these data suggest that the previously reported plasticity of the maternal brain may facilitate neural and behavioral recovery from neural insults.

Characteristic neurobiological patterns differentiate paternal responsiveness in two Peromyscus species.

Rodent paternal models provide unique opportunities to investigate the emergence of affiliative social behavior in mammals. Using biparental and uniparental Peromyscus species (californicus and maniculatus, respectively) we assessed paternal responsiveness by exposing males to biological offspring, unrelated conspecific pups, or familiar brothers following a 24-hour separation. The putative paternal circuit we investigated included brain areas involved in fear/anxiety [cingulate cortex (Cg), medial amygdala (MeA), paraventricular nucleus of the hypothalamus (PVN), and lateral septum (LS)], parental motivation [medial preoptic area (MPOA)], learning/behavioral plasticity (hippocampus), olfaction [pyriform cortex (PC)], and social rewards (nucleus accumbens). Paternal experience in californicus males reduced fos immunoreactivity (ir) in several fear/anxiety areas; additionally, all californicus groups exhibited decreased fos-ir in the PC. Enhanced arginine vasopressin (AVP) and oxytocin (OT)-ir cell bodies and fibers, as well as increased neuronal restructuring in the hippocampus, were also observed in californicus mice. Multidimensional scaling analyses revealed distinct brain activation profiles differentiating californicus biological fathers, pup-exposed virgins, and pup-naïve virgins. Specifically, associations among MPOA fos, CA1 fos, dentate gyrus GFAP, CA2 nestin-, and PVN OT-ir characterized biological fathers; LS fos-, Cg fos-, and AVP-ir characterized pup-exposed virgins, and PC-, PVN-, and MeA fos-ir characterized pup-naïve virgins. Thus, whereas fear/anxiety areas characterized pup-naïve males, neurobiological factors involved in more diverse functions such as learning, motivation, and nurturing responses characterized fatherhood in biparental californicus mice. Less distinct paternal-dependent activation patterns were observed in uniparental maniculatus mice. These data suggest that dual neurobiological circuits, leading to the inhibition of social-dependent anxiety as well as the activation of affiliative responses, characterize the transition from nonpaternal to paternal status in californicus mice.

Prior parity positively regulates learning and memory in young and middle-aged rats.

Reproductive experience in female rats modifies acquired behaviors, induces long-lasting functional neuroadaptations and can also modify spatial learning and memory. The present study supports and expands this knowledge base by employing the Morris water maze, which measures spatial memory. Age-matched young adult (YNG) nulliparous (NULL; nonmated) and primiparous (PRIM; one pregnancy and lactation) female rats were tested 15 d after the litter's weaning. In addition, corresponding middle-aged (AGD) PRIM (mated in young adulthood so that pregnancy, parturition, and lactation occurred at the same age as in YNG PRIM) and NULL female rats were tested at 18 mo of age. Behavioral evaluation included: 1) acquisition of reference memory (platform location was fixed for 14 to 19 d of testing); 2) retrieval of this information associated with extinction of the acquired response (probe test involving removal of the platform 24 h after the last training session); and 3) performance in a working memory version of the task (platform presented in a novel location every day for 13 d, and maintained in a fixed location within each day). YNG PRIM outperformed NULL rats and showed different behavioral strategies. These results may be related to changes in locomotor, mnemonic, and cognitive processes. In addition, YNG PRIM exhibited less anxiety-like behavior. Compared with YNG rats, AGD rats showed less behavioral flexibility but stronger memory consolidation. These data, which were obtained by using a well-documented spatial task, demonstrate long lasting modifications of behavioral strategies in both YNG and AGD rats associated with a single reproductive experience.

The construction of the maternal brain: theoretical comment on Kim et al. (2010).

Recently, there has been a spate of articles detailing the many and multifaceted alterations that define the Maternal Brain. The article by Kim et al. (2010) has provided a new "window" into the brain of the mother by the use of MRI showing structural changes in major regions over the period of the first few months, during which the intimate relationship between mother and infant forms. In this accompanying Commentary, we explore some connections between the animal work and the human data, and suggest some common pathways. In the end, it appears that maternal motivation, far from the intrinsic or instinctual state that many believe it to be, may, in fact, be attributable to many active processes "building" a responsive neural substrate. Like early brain development, itself a marvel of interacting genetic and environmental forces, the Maternal Brain may represent another developmental epoch in the life of the female. In this case, the alterations occur to promote the survival of subsequent generations and the care and protection of a most expensive mammalian metabolic and genetic investment. If so, is it possible that just as there are edifices that are poorly constructed and crumble at the first challenge by earthquake or hurricane, there may be defectively assembled maternal brains that fail in their task of caring adequately for young?

Neurobiological constituents of active, passive, and variable coping strategies in rats: integration of regional brain neuropeptide Y levels and cardiovascular responses.

Effective coping strategies build resilience against stress-induced pathology. In the current study, young male rats were categorized as active, passive, or variable copers by observing their responses to being gently restrained on their backs (i.e., the back-test). The rats were subsequently exposed to chronic unpredictable stress, which included several ethologically relevant stressors such as predator odors and calls, for approximately three weeks. During this time, the variable copers, defined as rats that demonstrated a variable as opposed to a rigid response to stress, exhibited more seemingly adaptive responsiveness in three successive forced swim tests than the more consistently responding passive and active copers. This behavioral flexibility was accompanied by increased neuropeptide Y-immunoreactivity in the bed nucleus of the stria terminalis (BNST) and the amygdala and increased fos-immunoreactivity in the BNST. Additionally, the alterations in fecal corticosteroid levels and cardiovascular measures (systolic blood pressure and tail blood volume) between baseline and stress conditions differed according to coping strategy. Factor analysis indicates that variable copers were characterized by a distinct cardiovascular and neural response to the stress exposure. These results suggest that this animal coping model may be useful in discerning the adaptive nature of particular response strategies in the face of environmental exigencies.

Reproductive experience and the response of female Sprague-Dawley rats to fear and stress.

The present work examines the relationship between reproductive experience (comprising breeding, parturition, and lactation) and the behavioral and hormonal processes of fear and stress in the female laboratory rat. Previous research has indicated that reproductive experience functions to decrease the female's stress response in potentially harmful environments, thereby providing her with numerous survival benefits, including decreased fearfulness, increased aggression, and refined hunting skills. This study was designed to determine how nulliparous (no reproductive experience), primiparous (1 reproductive experience) and multiparous (at least 2 reproductive experiences) rats respond to a Pavlovian paradigm of learned fear, involving the pairing of a neutral stimulus (conditioned stimulus) with an aversive stimulus (unconditioned stimulus). We report evidence that reproductive experience is linked with fear-response and anxiety-like behaviors. Our findings indicate that reproductive experience has an additive effect: primiparous mothers showed a different response to the paradigm of conditioned fear not only compared with those of nulliparous rats as well as multiparous mothers. Assessing the complex interconnections among the behavioral and physiologic measures recorded in this study, multidimensional scaling confirmed a clear separation among the 3 groups of rats in terms of the behavioral and physiologic responses to the experimental paradigm, supporting the conclusion that reproductive experience influences the maternal mind.

Reproduction-induced neuroplasticity: natural behavioural and neuronal alterations associated with the production and care of offspring.

As a female transitions into motherhood, many neurobiological adaptations are required to meet the demands presented by her offspring. In addition to the traditional maternal responses (e.g. crouching, nursing, retrieving, grooming), our laboratories have observed several behavioural modifications accompanying parity, especially in the areas of foraging and emotional resilience. Additionally, brain modifications have been observed in the hippocampus and amygdala, providing support for neural plasticity extending beyond the expected hypothalamic alterations. Interestingly, we have observed parenting-induced neuroplasticity to persist into late adulthood, even providing protection against age-related brain and memory deficits. Although the majority of work on the parental brain has been conducted on females, preliminary research suggests similar changes in the biparental male California deer mouse. Taken together, research suggests that the parental brain is dynamic and changeable as it undergoes diverse and, in some cases, long-lasting, modifications to facilitate the production and care of offspring.

Motherhood and the hormones of pregnancy modify concentrations of hippocampal neuronal dendritic spines.

Short-term fluctuations in steroid hormones such as estradiol (E2) and progesterone (P) can affect the concentration of hippocampal dendritic spines in adult, cycling nulliparous female rats. Pregnancy is characterized by a significantly longer duration of substantially elevated E2 and P compared to the estrous cycle. Thus, even greater changes than those reported during estrus may be evident. In two experiments, we examined the extent to which reproductive and hormonal state altered the concentration of apical neuronal dendritic spines of the CA1 region of the hippocampus in the following age-matched groups (N's = 7-10/group) of rats: in Exp. 1., CA1 dendritic spine density was examined in nulliparous diestrus (DES), proestrus (PRO), and estrus (ES) females, and late-pregnant (LP) (day 21) and lactating (day 5-6; LACT) females. In Exp. 2, the effects on spine density of a regimen mimicking pregnancy (and that stimulates maternal behavior) were examined, using ovariectomized, no hormone-exposed (OVX-minus) vs. sequential P&E(2)-treated (OVX + P&E2) groups. For both experiments, brains were removed, Golgi-Cox-stained and the most lateral tertiary branches of the apical dendrite of completely-stained hippocampal CA1 pyramidal neurons were traced with oil-immersion at x 1600 and dendritic spine density (# spines/10 micro dendritic segment) recorded. In Exp. 1, spine density was increased in LP and LACT females (which were not different) compared to the other virgin groups, including PRO females, who had more spines than DES and ES. In Exp. 2, OVX + P&E2 displayed significantly more dendritic spines per 10 micro than OVX-minus females (and had numbers that were similar to those of LP and LACT from Exp. 1). Pregnancy and its attendant hormonal fluctuations, therefore, may alter hippocampal neurons that regulate some non-pup-directed components of maternal behavior (e.g., nest building) or behaviors that support maternal behavior (e.g., foraging, associative memory).

Explorations of coping strategies, learned persistence, and resilience in Long-Evans rats: innate versus acquired characteristics.

In the current investigation, predispositions for coping styles (i.e., passive, flexible, and active) were determined in juvenile male rats. In subsequent behavioral tests, flexible copers exhibited more active responses. In another study, animals were exposed to chronic stress and flexible coping rats had lower levels of corticosteroids. Focusing on the acquired nature of coping strategies, rats receiving extensive training in a task requiring them to dig for food rewards (i.e., effort-based rewards) persisted longer in a challenging task than control animals. Thus, the results suggest that both predisposed coping strategies and acquired behavioral experience contribute to resilience in challenging situations.

Maternal experience produces long-lasting behavioral modifications in the rat.

From 5 to 22 months of age, cognitive and emotional responses of nulliparous, primiparous, and multiparous rats were assessed using a dry land maze (DLM) and an elevated plus-maze (EPM) at 4-month intervals. Parous rats exhibited improved spatial memory in the probe and competitive versions of the DLM, and more exploration in the EPM and a novel stimulus test relative to nulliparous females. The nulliparous females, however, outperformed parous rats during the DLM visual cue test at 17 months of age. At 23 months, no differences in stressed corticosterone levels or Golgi-stained hippocampal neurons were observed. Thus, cognitive and emotional modifications were observed in parous rats; the neurobiological mechanisms for these enduring effects, however, remain to be identified.

Single or multiple reproductive experiences attenuate neurobehavioral stress and fear responses in the female rat.

The female brain is a dynamic structure, which expresses its plasticity most readily following reproductive experience (RE). In Experiment 1, we generated nulliparous (NP), primiparous (PP), and multiparous (MP) females (none, one, and two litters, respectively). Two weeks following the weaning of the first/second six-pup litters, the age-matched MP and PP and the non-pup-exposed NP animals were subjected to a 60-min restraint stress paradigm (enclosure in a Plexiglas restraint tube). The brains were removed and processed for c-fos immunoreactivity (c-fos-IR) in CA3 region of the hippocampus (HI) and in basolateral amygdala (BLA). MP and PP females had very similar numbers of c-fos-IR neurons in both HI and BLA, whereas both were lower than NPs. In a second experiment, the same groups were generated, together with primigravid (PG; first pregnancy) and multigravid (MG; second pregnancy) females, tested in late pregnancy. The animals were exposed to a 30-min trial in an open field and were killed, and the brains were again examined for c-fos-IR. The parous and gravid animals displayed less reactivity to the stress of the open field (i.e., reductions in behavioral measures of anxiety) and significantly less c-fos expression in both CA3 and BLA. The gravid animals displayed significantly less c-fos expression in CA3 and BLA compared to parous females, although neither group differed as a result of a second RE. The data suggest that reproductive (viz., hormonal) and/or maternal (viz., pup exposure) experience may inure a female and her brain to stress, rendering her less susceptible to the behavioral-or other-disruptions that stress sensitivity can produce. Together, these data suggest that the experiences of motherhood (pregnancy, pup exposure, suckling stimulation, etc.) summate to produce reductions in anxiety and stress responsiveness that start before and last long after pup exposure and care. Such reductions may be adaptive in the face of demands placed upon the parous vs. the NP female.