Rewards are often unreliable and optimal choice requires behavioral flexibility and learning about the probabilistic nature of uncertain rewards. Probabilistic learning occurs over multiple trials, often without conscious knowledge, and is traditionally associated with striatal function. While the hippocampus is classically recognized for its role in memory for individual experiences, recent work indicates that it is also involved in probabilistic forms of learning but little is known about the features that support such learning. We hypothesized that adult neurogenesis may be involved, because adult-born neurons contribute to both learning and reward-related behaviors. To test this, we used an appetitive probabilistic reversal learning task where a correct lever is rewarded with 80% probability and an incorrect lever is rewarded with 20% probability. Behavioral flexibility was assessed by switching correct-incorrect lever identities after 8 consecutive correct choices. Transgenic male rats that lacked adult neurogenesis displayed an initial deficit in discriminating the correct and incorrect levers, but they were not impaired at reversing behavior when the reward contingencies switched. When reward was withheld after a correct lever choice, neurogenesis-deficient rats were more likely to choose the incorrect lever on the subsequent trial. Also, rats with intact neurogenesis were more sensitive to reward at the incorrect lever. Differences were not observed in control transgenic rats that had intact neurogenesis. These results identify a novel role for neurogenesis in learning about uncertain, probabilistic rewards. Altered sensitivity to reward and negative feedback furthermore implicates neurogenesis in cognitive phenotypes associated with mood disorders such as depression. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
ABSTRACT Adult hippocampal neurogenesis has been implicated in the spatial processing functions of the hippocampus but ablating neurogenesis does not consistently lead to behavioral deficits in spatial tasks. Parallel studies have shown that adult-born neurons also regulate behavioral responses to stressful and aversive stimuli. We therefore hypothesized that spatial functions of adult-born neurons may be more prominent under conditions of stress, and may differ between males and females given established sex differences in stress responding. To test this we trained intact and neurogenesis-deficient rats in the spatial water maze at temperatures that vary in their degree of aversiveness. At standard temperatures (25°C) ablating neurogenesis did not alter learning and memory in either sex, consistent with prior work. However, in cold water (16°C), ablating neurogenesis had divergent sex-dependent effects: relative to intact rats, male neurogenesis-deficient rats were slower to escape and female neurogenesis-deficient rats were faster. Neurogenesis promoted temperature-related changes in search strategy in females, but it promoted search strategy stability in males. Females displayed greater recruitment of the dorsal hippocampus than males, particularly at 16°C. However, blocking neurogenesis did not alter activity-dependent immediate-early gene expression in either sex. Finally, morphological analyses of retrovirally-labelled neurons revealed greater experience-dependent plasticity in new neurons in males. Neurons had comparable morphology in untrained rats but 16°C training increased spine density, and 25°C training caused shrinkage of mossy fiber presynaptic terminals, specifically in males. Collectively, these findings indicate that neurogenesis functions in memory are prominent under conditions of stress, they provide the first evidence for sex differences in the behavioral function of newborn neurons, and they suggest possibly distinct roles for neurogenesis in cognition and mental health in males and females.
Abstract The growth of research on adult neurogenesis and the development of new models and tools have greatly advanced our understanding of the function of newborn neurons in recent years. However, there are still significant limitations in the ability to identify the functions of adult neurogenesis in available models. Here we report a transgenic rat (TK rat) that expresses herpes simplex virus thymidine kinase in GFAP+ cells. Upon treating TK rats with the antiviral drug valganciclovir, granule cell neurogenesis can be completely inhibited in adulthood, in both the hippocampus and olfactory bulb. Interestingly, neurogenesis in the glomerular and external plexiform layers of the olfactory bulb was only partially inhibited, suggesting that some adult-born neurons in these regions derive from a distinct precursor population that does not express GFAP. Within the hippocampus, blockade of neurogenesis was rapid and nearly complete within 1 week of starting treatment. Preliminary behavioral analyses indicate that general anxiety levels and patterns of exploration are generally unaffected in neurogenesis-deficient rats. However, neurogenesis-deficient TK rats showed reduced sucrose preference, suggesting deficits in reward-related behaviors. We expect that TK rats will facilitate structural, physiological, and behavioral studies that complement those possible in existing models, broadly enhancing understanding of the function of adult neurogenesis.
Steroid hormones are vital for a successful pregnancy. The placenta is attached to the uterine wall and is the major organ of communication between the mother and the fetus through the umbilical cord and the transfer of compounds (including the production and actions of steroids) across the villous placenta. Therefore, a correct understanding and measurement of steroid levels across the maternal–placental–fetal interface is essential. We have experience spanning more than two decades and have published more than 40 papers using a variety of methods to assess circulating and placental steroid levels. In this review, we discuss various methods for steroid detection and quantitation, as well as their advantages and disadvantages. This document provides technical guidance for best practices that, in our estimation, can assist researchers in more easily and correctly performing these studies. Critical methodological considerations, including tissue collection, tissue processing, and analytical factors (sensitivity, selectivity, matrix effects, and internal standards), are covered. We highlight important differences between human and rodent tissues as they relate to steroid levels in pregnancy and the interpretation of results, and provide guidance for best practices in future studies.
ABSTRACT The dentate gyrus is essential for remembering the fine details of experiences that comprise episodic memory. Dentate gyrus granule cells receive highly-processed sensory information and are hypothesized to perform a pattern separation function, whereby similar sensory inputs are transformed into orthogonal neural representations. Behaviorally, this is believed to enable distinct memory for highly interfering stimuli. Since the dentate gyrus is comprised of a large number of adult-born neurons, which have unique synaptic wiring and neurophysiological firing patterns, it has been proposed that neurogenesis may contribute to this process in unique ways. Some behavioral evidence exists to support this role, whereby neurogenesis-deficient rodents are impaired at discriminating the fine visuospatial details of experiences. However, the extent to which newborn neurons contribute to dentate gyrus-dependent learning tasks is unclear. Furthermore, since most studies of dentate gyrus function are conducted in male rats, little is known about how females perform in similar situations, and whether there might be sex differences in the function of adult neurogenesis. To address these issues, we examined spatial discrimination memory in transgenic male and female rats that lacked adult neurogenesis. The first task probed memory for the position of local objects in an open field, assessed by behavioral responses to novel object locations. The second task examined memory for distal environmental cues. All rats were able to successfully discriminate local and distal cue changes. Males and females also performed comparably, although females displayed higher levels of rearing and locomotion. Collectively, our results indicate that rats are capable of learning about local and distal cues in the absence of adult neurogenesis.
During immature stages, adult-born neurons pass through critical periods for survival and plasticity. It is generally assumed that by 2 months of age adult-born neurons are mature and equivalent to the broader neuronal population, raising questions of how they might contribute to hippocampal function in old age when neurogenesis has declined. However, few have examined adult-born neurons beyond the critical period or directly compared them to neurons born in infancy. Here, we used a retrovirus to visualize functionally relevant morphological features of 2- to 24-week-old adult-born neurons in male rats. From 2 to 7 weeks, neurons grew and attained a relatively mature phenotype. However, several features of 7-week-old neurons suggested a later wave of growth: these neurons had larger nuclei, thicker dendrites, and more dendritic filopodia than all other groups. Indeed, between 7 and 24 weeks, adult-born neurons gained additional dendritic branches, formed a second primary dendrite, acquired more mushroom spines, and had enlarged mossy fiber presynaptic terminals. Compared with neonatal-born neurons, old adult-born neurons had greater spine density, larger presynaptic terminals, and more putative efferent filopodial contacts onto inhibitory neurons. By integrating rates of cell birth and growth across the life span, we estimate that adult neurogenesis ultimately produces half of the cells and the majority of spines in the dentate gyrus. Critically, protracted development contributes to the plasticity of the hippocampus through to the end of life, even after cell production declines. Persistent differences from neonatal-born neurons may additionally endow adult-born neurons with unique functions even after they have matured. SIGNIFICANCE STATEMENT Neurogenesis occurs in the hippocampus throughout adult life and contributes to memory and emotion. It is generally assumed that new neurons have the greatest impact on behavior when they are immature and plastic. However, since neurogenesis declines dramatically with age, it is unclear how they might contribute to behavior later in life when cell proliferation has slowed. Here we find that newborn neurons mature over many months in rats and may end up with distinct morphological features compared with neurons born in infancy. Using a mathematical model, we estimate that a large fraction of neurons is added in adulthood. Moreover, their extended growth produces a reserve of plasticity that persists even after neurogenesis has declined to low rates.
Abstract Consumption of sucrose (table sugar) is high in much of the world. The effects of a maternal diet high in sucrose on the placenta and fetal brain remain unknown. In rats, maternal consumption of sucrose at a human-relevant level has effects on the mother’s physiology and steroids, as well as long-lasting and sex-specific effects on the adult offspring’s brain and behavior. In the mothers, there are metabolic effects of sucrose intake, such as impaired glucose tolerance, increased liver lipids, and increased adipose inflammation. In rat dams, sucrose intake also decreases corticosterone levels in the blood but not in the brain. In the adult male offspring, preference for a high-sucrose diet and a high-fat diet increases due to maternal sucrose intake. In addition, maternal sucrose intake increases motivation for sugar rewards in a progressive ratio schedule of reinforcement in adult male offspring. In adult female offspring, corticosterone levels increase in the blood and brain as a result of maternal sucrose intake. In this study, we investigated the underlying mechanisms of the observed behavioral and endocrine effects in the adult offspring. Here, we examined cytokines and anti-inflammatory steroids in the placenta, amniotic fluid, and fetal blood and brain. In our model, we feed rat dams either a high-sucrose diet (26% of kCal) or an isocaloric, matched, control diet (1% sucrose) 10 weeks prior to and during gestation. At embryonic day 19 (E19), we collected maternal blood, placenta, amniotic fluid, fetal blood, and fetal brain. We use Palkovits punch to microdissect the placenta and fetal brain. Next, we use a liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay, which is highly precise and specific, to measure multiple steroids (e.g. corticosterone, progesterone, estradiol, allopregnanolone). The method is highly sensitive, and we can measure neurosteroids in multiple regions of the fetal brain (e.g. prefrontal cortex, nucleus accumbens, hypothalamus, hippocampus). Moreover, we will examine steroidogenic enzymes and cytokines in the fetal brain and placenta. Preliminary data show distinct steroid patterns in amniotic fluid and fetal blood, as well as in different parts of the placenta.
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