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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    486—Neural Mechanisms Mediating Fear and Anxiety

    Monday, November 11, 2013, 1:00 pm - 5:00 pm

    486.05: Independent hypothalamic circuits for social and predator fear

    Location: Halls B-H

    1EMBL Mouse Biol. Unit, Monterotondo, Italy; 2EMBL, Monterotondo, Italy; 3Univ. of Sao Pulo, Sao Paulo, Brazil

    Abstract Body: Fear is a distressing negative sensation induced by a wide variety of perceived threats, including predators, aggressive members of the same species, and potentially harmful inanimate stimuli. The neural substrates of fear have been widely investigated using footshock-based paradigms that have implicated the amygdala in its encoding and expression. However, predator and social threats, unlike physically harmful threats, activate distinct sub-nuclei of the ventromedial hypothalamus (VMH), a structure critical for motivated behaviors such as feeding, sex, and aggression. This observation raises the question of whether distinct circuits within the brain process different fear-inducing threats and furthermore suggests an unappreciated role for VMH in fear. Here we established a behavioral test method to measure approach-avoidance responses to painful, predator, and aggressive conspecific threats and applied cell-type specific neural inhibition tools to demonstrate of a double dissociation of VMH sub-nuclei in predator and conspecific fear. These data demonstrate that functionally separable circuits in the VMH are critical for processing fear to different classes of threat and underscores the multi-modal function of the medial hypothalamus in controlling motivated behavior.

    Lay Language Summary: Our research indicates that
    predator and social fear are processed in the ventromedial hypothalamus, a nucleus
    previously implicated in feeding, sex and aggression. Additionally we
    demonstrated that functionally independent populations of neurons within this
    nucleus are essential for fear to different threats.
    Fear is an emotion that is necessary for
    the survival of the individual because it guarantees adaptive responses to life
    challenging threats. However, fear can also become excessive or inappropriate,
    such as experienced in persons suffering from social phobias, panic disorder,
    and other mental illnesses. Fear has been widely investigated in animals using
    electrical shocks and these studies point to neural circuits in the amygdala as
    a critical brain structure for fear responding and learning. However, these
    circuits are not necessary for fear responses to threats from predators or
    aggressive members of the same species, suggesting that other neural circuits
    mediate the fear typically described in humans. Our study provides the first
    evidence that predator and social fear are encoded in independent circuits in
    the medial hypothalamus. This evidence carries implications for the
    selective intervention in pathological fear in humans.

    In order to study the neural basis of fear
    to different threats we developed a novel behavioral test that measures fear
    responses to predators, aggressive members of the same species, and electric foot
    shock in mice. We subsequently created tools to selectively inhibit specific
    hypothalamic nuclei and test their involvement in fear to different threats. Specifically,
    we used transgenic and viral technology to deliver an engineered inhibitory
    receptor either to the dorsomedial or to the ventrolateral part of the
    ventromedial hypothalamus, a region that has previously been implicated in
    feeding, sex, and aggression, but that has also been shown to become activated by
    social and predator threats. Injection of the otherwise biologically inert
    ligand, clozapine-N-oxide, caused a rapid and reversible activation of the
    engineered receptor and inhibition of neuronal activity, allowing us to
    determine their role in fear.
    We observed that inhibition of the
    dorsomedial part of the ventromedial hypothalamus, previously implicated in
    feeding, blocked predator fear, while inhibition of the ventrolateral part, previously
    implicated in sex and aggression, impaired social fear - thereby demonstrating
    a double dissociation of neural circuits supporting social and predator fear. Importantly,
    neither manipulation impaired fear of an electric foot shock.
    We are currently investigating whether fear
    to different threats is also handled by distinct circuits in brain structures
    downstream of the hypothalamus that are responsible for producing the flight
    and freezing behavior involved in fear responses. In particular we are focusing
    on the periaqueductal grey, a downstream structure involved in motor pattern
    initiation and shown to be critical for the expression of fear responses. Intriguingly,
    electrical stimulation of either the ventromedial hypothalamus or
    periaqueductal grey in humans elicits panic attacks or the sensation of being
    chased, suggesting that similar circuits are likely to be important for fear in
    our species. Our studies argue that drugs that interfere with the activity of
    these structures could be used to selectively block fear in humans and
    potentially serve as treatments for pathological fear in mental illness.