Tracey J. Shors

Neurogenesis in the adult is involved in the formation of trace memories

The vertebrate brain continues to produce new neurons throughout life. In the rat hippocampus, several thousand are produced each day, many of which die within weeks. Associative learning can enhance their survival; however, until now it was unknown whether new neurons are involved in memory formation. Here we show that a substantial reduction in the number of newly generated neurons in the adult rat impairs hippocampal-dependent trace conditioning, a task in which an animal must associate stimuli that are separated in time. A similar reduction did not affect learning when the same stimuli are not separated in time, a task that is hippocampal-independent. The reduction in neurogenesis did not induce death of mature hippocampal neurons or permanently alter neurophysiological properties of the CA1 region, such as long-term potentiation. Moreover, recovery of cell production was associated with the ability to acquire trace memories. These results indicate that newly generated neurons in the adult are not only affected by the formation of a hippocampal-dependent memory, but also participate in it.

Learning enhances adult neurogenesis in the hippocampal formation.

Thousands of hippocampal neurons are born in adulthood, suggesting that new cells could be important for hippocampal function. To determine whether hippocampus-dependent learning affects adult-generated neurons, we examined the fate of new cells labeled with the thymidine analog bromodeoxyuridine following specific behavioral tasks. Here we report that the number of adult-generated neurons doubles in the rat dentate gyrus in response to training on associative learning tasks that require the hippocampus. In contrast, training on associative learning tasks that do not require the hippocampus did not alter the number of new cells. These findings indicate that adult-generated hippocampal neurons are specifically affected by, and potentially involved in, associative memory formation.

Neurogenesis in adulthood: a possible role in learning

The role of the hippocampal formation in learning and memory has long been recognized. However, despite decades of intensive research, the neurobiological basis of this process in the hippocampus remains enigmatic. Over 30 years ago, the production of new neurons was found to occur in the brains of adult rodents. More recently, the documentation of adult neurogenesis in the hippocampal formation of a variety of mammals, including humans, has suggested a novel approach towards understanding the biological bases of hippocampal function. Contemporary theories of hippocampal function include an important role for this brain region in associative learning. The addition of new neurons and consequently, their novel contribution to hippocampal circuitry could conceivably be a mechanism for relating spatially or temporally disparate events. In this review, we examine several lines of evidence suggesting that adult-generated neurons are involved in hippocampal-dependent learning. In particular, we examine the variables that modulate hippocampal neurogenesis in adulthood and their relation to learning and memory.

Learning Enhances the Survival of New Neurons beyond the Time when the Hippocampus Is Required for Memory

Trace memories are formed when a stimulus event becomes associated with another event that occurs later in time and is discontinuous with the first event. The formation of trace memories enhances the survival of newly generated neurons in the dentate gyrus of the adult hippocampus (Gould et al., 1999a). Here we tested whether the acquisition of trace memories early during training is sufficient to enhance cell survival. We also examined whether the new neurons affected by trace memory formation persist indefinitely or only as long as the hippocampus is necessary for the expression of those memories. Groups of adult rats were injected with bromodeoxyuridine (BrdU), a marker of dividing cells, and trained 1 week later with paired stimuli using a trace eyeblink conditioning task or exposed to the same number of unpaired stimuli. Cell survival was assessed after different numbers of training trials and survival periods after training. Overall cell survival was not enhanced by exposure to 200 trials of paired stimuli during trace conditioning. However, there was a positive correlation between performance of individual animals and cell survival. In addition, exposure to 800 trials of paired stimuli during trace conditioning increased the number of BrdU-labeled cells 60 d after training. The vast majority of these cells were neurons and coexpressed the neuronal markers class IIIβ-tubulin or neuronal nuclei. These data suggest that individual differences in associative learning predict whether new neurons will survive and that once affected, these neurons remain for months and beyond the time when they are required for the retention of trace memories.

Sex differences in learning processes of classical and operant conditioning

Males and females learn and remember differently at different times in their lives. These differences occur in most species, from invertebrates to humans. We review here sex differences as they occur in laboratory rodent species. We focus on classical and operant conditioning paradigms, including classical eyeblink conditioning, fear-conditioning, active avoidance and conditioned taste aversion. Sex differences have been reported during acquisition, retention and extinction in most of these paradigms. In general, females perform better than males in the classical eyeblink conditioning, in fear-potentiated startle and in most operant conditioning tasks, such as the active avoidance test. However, in the classical fear-conditioning paradigm, in certain lever-pressing paradigms and in the conditioned taste aversion, males outperform females or are more resistant to extinction. Most sex differences in conditioning are dependent on organizational effects of gonadal hormones during early development of the brain, in addition to modulation by activational effects during puberty and adulthood. Critically, sex differences in performance account for some of the reported effects on learning and these are discussed throughout the review. Because so many mental disorders are more prevalent in one sex than the other, it is important to consider sex differences in learning when applying animal models of learning for these disorders. Finally, we discuss how sex differences in learning continue to alter the brain throughout the lifespan. Thus, sex differences in learning are not only mediated by sex differences in the brain, but also contribute to them.

The contribution of adrenal and reproductive hormones to the opposing effects of stress on trace conditioning in males versus females.

Exposure to an acute stressful experience facilitates classical conditioning in male rats but impairs conditioning in female rats (T. J. Shors, C. Lewczyk, M. Paczynski, P. R. Mathew, & J. Pickett, 1998; G. E. Wood & T. J. Shors, 1998). The authors report that these effects extend to performance on the hippocampal-dependent task of trace conditioning. The stress-induced impairment of conditioning in females was evident immediately, 24 hr and 48 hr after stress, depending on the stage of estrus. Moreover, the effect could be reactivated days later by reexposure to the stressful context. Corticosterone levels correlated with overall performance in males but not in females. Unlike the effect seen in males, adrenalectomy did not prevent the stress-induced effect on conditioning in females. These data indicate that exposure to the same experience can have opposite effects on learning in males versus females and that these opposing effects are mediated by differing hormonal systems.

Acute Stress Rapidly and Persistently Enhances Memory Formation in the Male Rat

Previous studies, as well as the present one, report that acute exposure to intermittent tailshocks enhances classical eyeblink conditioning in male rats when trained 24 h after stressor cessation. In Experiment 1, it was determined that the facilitating effect of stress on conditioning could also be obtained in response to a stressor of acute inescapable swim stress but not inescapable noise or the unconditioned stimulus of periorbital eyelid stimulation. These selective responses arose despite comparable enhancements of the stress-related hormone corticosterone in response to tailshocks, periorbital eyelid stimulation, noise stress, and supraelevation in response to swim stress. Although corticosterone is necessary for the enhanced learning in response to stress (Beylin & Shors, 1999), these results suggest that it is not sufficient. In addition, the results suggest that the enhancement is not dependent on common characteristics between the stressor and the conditioning stimuli (stimulus generalization). In Experiment 2, it was determined that the facilitating effect of the stressor on conditioning occurs within 30 min of stressor cessation. Thus, the mechanism responsible for facilitating memory formation is rapidly induced as well as persistently expressed. In Experiment 3, it was determined that exposure to the stressor does not enhance performance of the conditioned response after the response has been acquired. Thus, exposure to the stressor enhances the formation of new associations rather than affecting retention or performance of the motor response. These studies extend the circumstances under which stress is known to enhance associative learning and implicate neural mechanisms of memory enhancement that are rapidly induced and persistently expressed.

Stages of estrous mediate the stress-induced impairment of associative learning in the female rat

EXPOSURE to a stressful event facilitates classical eyeblink conditioning in male rats and impairs conditioning in females. The contribution of stages of estrous to the stress-induced impairment of eyeblink conditioning was evaluated. Females in proestrus, estrus and diestrus were either exposed to an acute stressor of intermittent tailshocks or swim stress and compared to unstressed females in the three stages. Females in proestrus, when estrogen levels are high, acquired the conditioned response at a facilitated rate relative to females in other stages. However, exposure to a stressor of either intermittent tailshocks or inescapable swim stress severely impaired acquisition in females during proestrus. These results suggest that the enhancing effect of estrogen on procedural memory formation is disrupted by previous exposure to a stressful event.

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.

Glucocorticoids are necessary for enhancing the acquisition of associative memories after acute stressful experience

Exposure to acute stressful experience can enhance the later ability to acquire new memories about associations between stimuli. This enhanced learning is observed during classical eyeblink conditioning of both hippocampal-dependent and -independent learning. It can be induced within minutes of the stressful event and persists for days. Here we examined the role of the major stress hormones glucocorticoids in the enhancement of learning after stress. In the first two experiments, it was determined that adrenalectomy (ADX), with and without replacement of basal levels of corticosterone, prevented the stress-induced enhancement of trace conditioning, a task that is dependent on the hippocampus for acquisition. In a third experiment, demedullation, which removes the adrenal medulla but leaves the adrenal cortex and corticosterone levels intact, did not affect the enhancement of learning after stress. In a fourth experiment, ADX prevented the stress-induced enhancement of delay conditioning, a hippocampal-independent task. In a final experiment, it was determined that one injection of stress levels of corticosterone enhanced new learning within minutes but not new learning 24 h later. Together these results suggest that endogenous glucocorticoids are necessary and sufficient for transiently enhancing acquisition of new associative memories and necessary but insufficient for persistently enhancing their acquisition after exposure to an acute stressful experience.