Uncontrollable stress has been recognized to influence the hippocampus at various levels of analysis. Behaviorally, human and animal studies have found that stress generally impairs various hippocampal-dependent memory tasks. Neurally, animal studies have revealed that stress alters ensuing synaptic plasticity and firing properties of hippocampal neurons. Structurally, human and animal studies have shown that stress changes neuronal morphology, suppresses neuronal proliferation, and reduces hippocampal volume. Since the inception of stress research nearly 80 years ago, much focus has been on the varying levels of hypothalamic-pituitary-adrenal (HPA) axis neuroendocrine hormones, namely glucocorticoids, as mediators of the myriad stress effects on the hippocampus and as contributing factors to stress-associated psychopathologies such as post-traumatic stress disorder (PTSD). However, reports of glucocorticoid-produced alterations in hippocampal functioning vary widely across studies. This review provides a brief history of stress research, examines how the glucocorticoid hypothesis emerged and guides contemporary stress research, and considers alternative approaches to understanding the mechanisms underlying stress effects on hippocampal functioning.

The periaqueductal gray (PAG) and amygdala are known to be important for defensive responses, and many contemporary fearconditioning models present the PAG as downstream of the amygdala, directing the appropriate behavior (i.e., freezing or fleeing). However, empirical studies of this circuitry are inconsistent and warrant further examination. Hence, the present study investigated the functional relationship between the PAG and amygdala in two different settings, fear conditioning and naturalistic foraging, in rats. In fear conditioning, electrical stimulation of the dorsal PAG (dPAG) produced unconditional responses (URs) composed of brief activity bursts followed by freezing and 22-kHz ultrasonic vocalization. In contrast, stimulation of ventral PAG and the basolateral amygdalar complex (BLA) evoked freezing and/or ultrasonic vocalization. Whereas dPAG stimulation served as an effective unconditional stimulus for fear conditioning to tone and context conditional stimuli, neither ventral PAG nor BLA stimulation supported fear conditioning. The conditioning effect of dPAG, however, was abolished by inactivation of the BLA. In a foraging task, dPAG and BLA stimulation evoked only fleeing toward the nest. Amygdalar lesion/inactivation blocked the UR of dPAG stimulation, but dPAG lesions did not block the UR of BLA stimulation. Furthermore, in vivo recordings demonstrated that electrical priming of the dPAG can modulate plasticity of subiculum-BLA synapses, providing additional evidence that the amygdala is downstream of the dPAG. These results suggest that the dPAG conveys unconditional stimulus information to the BLA, which directs both innate and learned fear responses, and that brain stimulation-evoked behaviors are modulated by context. fear circuitry | learning and memory | long-term depression | long-term potentiation | synaptic plasticity D ecades of research involving various techniques have identified that the amygdala is essential for both innate and learned fear (1). Evidence indicates that neurons in the basolateral amygdalar complex (BLA) (basal and lateral nuclei) (2) are responsive to both the conditional stimulus (CS) and unconditional stimulus (US) (3, 4), undergo plastic changes during fear conditioning (5), and are necessary for producing fear responses (6, 7). Indeed, a recent study has shown that optogenetically induced depolarization of pyramidal neurons in the lateral amygdala (LA) can elicit a fear unconditional response (UR) and, when repeatedly paired with auditory CS, supports fear conditioning via Hebbian-like synaptic plasticity (8).However, stimulation-induced fear conditioning is not only achievable through the amygdala. Other studies have found that stimulation of the dorsal periaqueductal gray (dPAG) is an effective US in fear conditioning (9, 10). The PAG has long been implicated in generating defensive behaviors (11), and it has been suggested that its stimulation can support fear conditioning to a CS because it transmits the aversive US information to the LA (9, 12). Some have a...

Foraging-associated predation risk is a natural problem all prey must face. Fear evolved due to its protective functions, guiding and shaping behaviors that help animals adapt to various ecological challenges. Despite the breadth of risky situations in nature that demand diversity in fear behaviors, contemporary neurobiological models of fear stem largely from Pavlovian fear conditioning studies that focus on how a particular cue becomes capable of eliciting learned fear responses, thus oversimplifying the brain’s fear system. Here we review fear from functional, mechanistic, and phylogenetic perspectives where environmental threats cause animals to alter their foraging strategies in terms of spatial and temporal navigation, and discuss whether the inferences we draw from fear conditioning studies operate in the natural world.

The scientific understanding of fear and anxiety—in both normal and pathological forms—is presently limited by a predominance of studies that use male animals and Pavlovian fear conditioning-centered paradigms that restrict and assess specific behaviors (e.g., freezing) over brief sampling periods and overlook the broader contributions of the spatiotemporal context to an animal’s behavioral responses to threats. Here, we use a risky “closed economy” system, in which the need to acquire food and water and the need to avoid threats are simultaneously integrated into the lives of rats, to examine sex differences in mitigating threat risk while foraging. Rats lived for an extended period (∼2 months) in enlarged chambers that consisted of a safe, bedded nest and a risky foraging area where footshocks could be delivered unpredictably. We observed that male and female rats used different strategies for responding to the threat of footshock. Whereas male rats increased the size of meals consumed to reduce the overall time spent foraging, female rats sacrificed their metabolic needs in order to avoid shocks. Ovarian hormone fluctuations were shown to exert slight but reliable rhythmic effects on risky decision-making in gonadally intact female rats. However, this did not produce significant differences in approach–avoidance trade-offs between ovariectomized and intact female groups, suggesting that male–female sex differences are not due to the activational effects of gonadal hormones but, rather, are likely to be organized during early development.

Virtually all animals have endogenous clock mechanisms that “entrain” to the light-dark (LD) cycle and synchronize psychophysiological functions to optimal times for exploring resources and avoiding dangers in the environment. Such circadian rhythms are vital to human mental health, but it is unknown whether circadian rhythms “entrained” to the LD cycle can be overridden by entrainment to daily recurring threats. We show that unsignaled nocturnal footshock caused rats living in an “ethological” apparatus to switch their natural foraging behavior from the dark to the light phase and that this switch was maintained as a free-running circadian rhythm upon removal of light cues and footshocks. Furthermore, this fear-entrained circadian behavior was dependent on an intact amygdala and suprachiasmatic nucleus. Thus, time-specific fear can act as a non-photic entraining stimulus for the circadian system, and limbic centers encoding aversive information are likely part of the circadian oscillator network that temporally organizes behavior.