Fear, a negative emotion triggered by dangerous stimuli, can lead to psychiatric disorders such as phobias, anxiety disorders, and depression. Investigating the neural circuitry underlying congenital fear can offer insights into the pathophysiological mechanisms of related psychiatric conditions. Research on innate fear primarily centers on the response mechanisms to various sensory signals, including olfactory, visual and auditory stimuli. Different types of fear signal inputs are regulated by distinct neural circuits. The neural circuits of the main and accessory olfactory systems receive and process olfactory stimuli, mediating defensive responses like freezing. Escape behaviors elicited by visual stimuli are primarily regulated through the superior colliculus and hypothalamic projection circuits. Auditory stimuli-induced responses, including escape, are mainly mediated through auditory cortex projection circuits. In this article, we review the research progress on neural circuits of innate fear defensive behaviors in animals. We further discuss the different sensory systems, especially the projection circuits of olfactory, visual and auditory systems, to provide references for the mechanistic study of related mental disorders.
Animals ; Humans ; Fear/physiology* ; Nerve Net

Fear memory contextualization is critical for selecting adaptive behavior to survive. Contextual fear conditioning (CFC) is a classical model for elucidating related underlying neuronal circuits. The primary visual cortex (V1) is the primary cortical region for contextual visual inputs, but its role in CFC is poorly understood. Here, our experiments demonstrated that bilateral inactivation of V1 in mice impaired CFC retrieval, and both CFC learning and extinction increased the turnover rate of axonal boutons in V1. The frequency of neuronal Ca²⁺ activity decreased after CFC learning, while CFC extinction reversed the decrease and raised it to the naïve level. Contrary to control mice, the frequency of neuronal Ca²⁺ activity increased after CFC learning in microglia-depleted mice and was maintained after CFC extinction, indicating that microglial depletion alters CFC learning and the frequency response pattern of extinction-induced Ca²⁺ activity. These findings reveal a critical role of microglia in neocortical information processing in V1, and suggest potential approaches for cellular-based manipulation of acquired fear memory.
Mice ; Animals ; Primary Visual Cortex ; Extinction, Psychological/physiology* ; Learning/physiology* ; Fear/physiology* ; Hippocampus/physiology*

Environmental threats often trigger innate defensive responses in mammals. However, the gradual development of functional properties of these responses during the postnatal development stage remains unclear. Here, we report that looming stimulation in mice evoked flight behavior commencing at P14-16 and had fully developed by P20-24. The visual-evoked innate defensive response was not significantly altered by sensory deprivation at an early postnatal stage. Furthermore, the percentages of wide-field and horizontal cells in the superior colliculus were notably elevated at P20-24. Our findings define a developmental time window for the formation of the visual innate defense response during the early postnatal period and provide important insight into the underlying mechanism.
Animals ; Evoked Potentials, Visual ; Fear/physiology* ; Mammals ; Mice ; Mice, Inbred C57BL ; Neurons/physiology* ; Superior Colliculi/physiology*

Defensive behaviors induced by innate fear or Pavlovian fear conditioning are crucial for animals to avoid threats and ensure survival. The zona incerta (ZI) has been demonstrated to play important roles in fear learning and fear memory, as well as modulating auditory-induced innate defensive behavior. However, whether the neuronal subtypes in the ZI and specific circuits can mediate the innate fear response is largely unknown. Here, we found that somatostatin (SST)-positive neurons in the rostral ZI of mice were activated by a visual innate fear stimulus. Optogenetic inhibition of SST-positive neurons in the rostral ZI resulted in reduced flight responses to an overhead looming stimulus. Optogenetic activation of SST-positive neurons in the rostral ZI induced fear-like defensive behavior including increased immobility and bradycardia. In addition, we demonstrated that manipulation of the GABAergic projections from SST-positive neurons in the rostral ZI to the downstream nucleus reuniens (Re) mediated fear-like defensive behavior. Retrograde trans-synaptic tracing also revealed looming stimulus-activated neurons in the superior colliculus (SC) that projected to the Re-projecting SST-positive neurons in the rostral ZI (SC-ZIr^SST-Re pathway). Together, our study elucidates the function of SST-positive neurons in the rostral ZI and the SC-ZIr^SST-Re tri-synaptic circuit in mediating the innate fear response.
Mice ; Animals ; Zona Incerta/metabolism* ; Neurons/metabolism* ; Fear/physiology* ; Somatostatin/metabolism*

Animals ; Avoidance Learning ; physiology ; Cues ; Extinction, Psychological ; physiology ; Fear ; physiology ; Male ; Mental Recall ; physiology ; Rats ; Sleep Deprivation ; physiopathology ; Sleep, REM ; physiology

Animals ; Extinction, Psychological ; physiology ; Fear ; physiology ; Male ; Mental Recall ; physiology ; Rats ; Rats, Sprague-Dawley ; Sleep Deprivation ; complications ; physiopathology ; Sleep, REM ; physiology

Animals ; Conditioning (Psychology) ; drug effects ; Extinction, Psychological ; drug effects ; physiology ; Fear ; drug effects ; physiology ; Male ; Mifepristone ; pharmacology ; Rats ; Rats, Sprague-Dawley

Rac1 belongs to the family of Rho GTPases, and plays important roles in the brain function. It affects the cell migration and axon guidance via regulating the cytoskeleton and cellular morphology. However, the effect of its dynamic activation in regulating physiological function remains unclear. Recently, a photoactivatable analogue of Rac1 (PA-Rac1) has been developed, allowing the activation of Rac1 by the specific wavelength of light in living cells. Thus, we constructed recombinant adeno-associated virus (AAV) of PA-Rac1 and its light-insensitive mutant PA-Rac1-C450A under the control of the mouse glial fibrillary acidic protein (mGFAP) promoter to manipulate Rac1 activity in astrocytes by optical stimulation. Primary culture of hippocampal astrocytes was infected with the recombinant AAV-PA-Rac1 or AAV-PA-Rac1-C450A. Real-time fluorescence imaging showed that the cell membrane of the astrocyte expressing PA-Rac1 protruded near the light spot, while the astrocyte expressing PA-Rac1-C450A did not. We injected AAV-PA-Rac1 and AAV-PA-Rac1-C450A into dorsal hippocampus to investigate the role of the activation of Rac1 in regulating the associative learning. With optical stimulation, the PA-Rac1 group, rather than the PA-Rac1-C450A group, showed slower learning curve during the fear conditioning compared with the control group, indicating that activating astrocytic Rac1 blocks the formation of contextual memory. Our data suggest that the activation of Rac1 in dorsal hippocampal astrocyte plays an important role in the associative learning.
Animals ; Astrocytes ; physiology ; Cell Membrane ; Cell Movement ; Conditioning, Classical ; Cytoskeleton ; Dependovirus ; Fear ; Hippocampus ; physiology ; Memory ; Mice ; Mice, Inbred C57BL ; Neuropeptides ; genetics ; physiology ; Optogenetics ; rac1 GTP-Binding Protein ; genetics ; physiology

Brain-derived neurotrophic factor (BDNF), a small dimeric secretory protein, plays a vital role in activity-dependent synaptic plasticity, learning and memory. It has been shown that BDNF in the hippocampus and amygdala participates in the formation of fear memory. However, little is known about the functional role of BDNF in the anterior cingulate cortex (ACC). To address this question, we examined the mRNA and protein levels of BDNF in the ACC of rats at various time points after fear conditioning, using quantitative real-time PCR and enzyme-linked immunosorbent assay (ELISA). The results showed that BDNF exhibited a temporally specific increase in both mRNA and protein levels after CS (tone) and US (foot shock) was paired. Such increase did not occur after the animals were exposed to CS or US alone. When BDNF antibody was locally infused into the ACC prior to CS-US pairing, both contextual and auditory fear memories were severely impaired. Taken together, these results suggest that BDNF in the ACC is required for the formation of fear memory.
Animals ; Brain-Derived Neurotrophic Factor ; metabolism ; Enzyme-Linked Immunosorbent Assay ; Fear ; Gyrus Cinguli ; metabolism ; Memory ; physiology ; RNA, Messenger ; metabolism ; Rats ; Real-Time Polymerase Chain Reaction

AIMTo study the effect of acute fear stress on emotional behaviors, Hormone levels, and the expression and activation of cerebra Erk1/2 of rats in vivo.

METHODSFourty eight male SD rats were divided randomly into control group and stress group. Rats of stress group received 30 min' s acute stress including foot shock and white noise, and then the emotional behaviors were observed. The hormone level in plasm and brain was determined by spectrophotofluorometry and radioimmunoassay kit. In the following experiments, Western blot was performed to determine the expression and phosphorylation of extracellular signal-regulated protein kinase (Erk) of four different regions of the brain.

RESULTSRats tested after acute fear stress displayed substantial decreases in open-field activity, increases in resistance to capture, and increases in fright reaction (P < 0.01). The stress also resulted in significantly higher plasmic and cerebral noradrenaline, corticosteroid, 5-hydroxytryptamine levels, and lower adrenomedulin level in comparison with the control (P < 0.01) after stress. At the time point of 0 min and 30 min after stress, the phosphorylation of Erk1/2 were increased in all four brain regions examined (hippocampus, striatum, prefrontal cortex and cerebellum).

CONCLUSIONAcute fear stress can induce abnormalities of emotional behaviors, such as behavioral habits, anxiety and defense, startle and delayed adaptation to startle, as well as the alteration of hormone levels. The phosphorylation of Erk1/2 may play a role in the abnormality of emotional behaviors of rats induced by acute fear stress.

Animals ; Anxiety ; Behavior, Animal ; Brain ; metabolism ; physiopathology ; Fear ; physiology ; Hormones ; analysis ; blood ; MAP Kinase Signaling System ; Male ; Motor Activity ; Phosphorylation ; Rats ; Rats, Sprague-Dawley ; Reflex, Startle ; Stress, Psychological ; metabolism ; physiopathology