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
*B. A. SILVA1, C. MATTUCCI2, N. CANTERAS3, C. GROSS2; 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.
Neuroscience 2013 (43rd annual meeting of the Society for Neuroscience)Exit