Identification Of Neuronal-circuits Of Innate Fear Provoked By Predator Odor

The term ’fear’ is used to describe the feeling that arises when we experience an impending threat to our survival. It is a very important defense mechanism for mammalian to cope with dangers that threatened to healthy survive. Fear is central to mammalian evolution. Abnormal fear in humans, particularly phobias and panic disorders is strongly associated with anxiety disorders and depression in clinical. Fear was divided to innate fear and conditioned fear according to the features of heritability and natural acquisition. Extensive studies have shown that the amygdala has a central role in processing conditioned fear. Lesion of amygdala dramatically blocked fear-conditioned responses. However, lesion of amygdala did not interfere with fear responses to predator odor. This evidence suggests that distinct neuronal circuits are responsible for conditioned fear and innate fear, the underlying neuronal circuitry is still largely unknown.To explore the neuronal circuitry for olfactory cue-induced innate fear in rodents, we first studied the c-fos protein expression pattern in the whole brain provoked by the pungent odor TMT. Due its unpleasant smell as sulfide, we used β-mercaptoethanol (ME), which also has a pungent odor but did not induce freezing behavior in mice, as an odor control and saline as a blank control. Compared with saline and ME stimuli, many brain nucleus were excited by TMT. However, we found that TMT exposure specifically induced massive c-fos expression in the lateral habenular nucleus (LHb), lateral hypothalamic area (LH), dorsomedial part of the ventromedial hypothalamic nucleus (VMHDM), and laterodorsal tegmental nucleus (LDT). It remains us that those nucleuses may play important and special roles in regulating innate fear.In order to investigate the mechanisms of innate fear neuronal circuitry; Combination of vivo ontogenetic manipulations, neurobehavioral assays, electrophysiology, mono-synaptic tracing virus and immunochemistry and so on, we found that activation of PV+ GABAergic neurons by glutamatergic inputs from the LHb as the upstream nucleus of LDT could rapidly induce freezing-like behavior. Photostimulation of SOM+ GABAergic neurons or silence of neuronal activity of PV+ GABAergic neurons markedly reduced the freezing-time of TMT-induced, but did not affect the freezing behavior induced by an auditory cue in mice with previous fear-conditioned learning. In the LDT, GABAergic microcircuits asymmetric selectivity inhibition of different subtypes excitatory neurons have synaptic connection with excitatory neurons in the LH and VMH precisely regulated freezing and fleeing behaviors.Here, our works for the first time identify that:1, LHb-LDT-Hypothalamus circuitry regulates innate defensive behavior; 2, GABAergic micro-circuitry plays important role in regulating distinct defensive behaviors; 3, proposing new strategy to divide excitatory neurons into different subtypes; 4, exploring how brain controls distinct behaviors via different subtypes neurons.