Electrical stimulation of certain hypothalamic regions in cats and rodents can elicit attack behaviour, but the exact location of relevant cells within these regions, their requirement for naturally occurring aggression and their relationship to mating circuits have not been clear. Genetic methods for neural circuit manipulation in mice provide a potentially powerful approach to this problem, but brain-stimulation-evoked aggression has never been demonstrated in this species. Here we show that optogenetic, but not electrical, stimulation of neurons in the ventromedial hypothalamus, ventrolateral subdivision (VMHvl) causes male mice to attack both females and inanimate objects, as well as males. Pharmacogenetic silencing of VMHvl reversibly inhibits inter-male aggression. Immediate early gene analysis and single unit recordings from VMHvl during social interactions reveal overlapping but distinct neuronal subpopulations involved in fighting and mating. Neurons activated during attack are inhibited during mating, suggesting a potential neural substrate for competition between these opponent social behaviours.
At a glance
- 1951) The study of instinct (Clarendon Press/Oxford University Press,
- Stammganglien-Reizversuche. Berichte der gesamten. Physiologie 42, 554–555 (1928)
- Das subkortikale Zentrum der affecktiven Abwehr-reaktion. Helv. Physiol. Acta I, 33–52 (1943) &
- Neurochemical characterization of hypothalamic neurons involved in attack behavior: glutamatergic dominance and co-expression of thyrotropin-releasing hormone in a subset of glutamatergic neurons. Neuroscience 133, 657–666 (2005) et al.
- Discriminant analysis of the localization of aggression-inducing electrode placements in the hypothalamus of male rats. Brain Res. 260, 61–79 (1983) et al.
- Ethology and pharmacology of hypothalamic aggression in the rat. Neurosci. Biobehav. Rev. 15, 527–538 (1991)
- Hypothalamic substrates for brain stimulation-induced attack, teeth-chattering and social grooming in the rat. Brain Res. 449, 311–327 (1988) , , &
- Neuropharmacology of brain-stimulation-evoked aggression. Neurosci. Biobehav. Rev. 23, 359–389 (1999) , , &
- Cerebral hemisphere regulation of motivated behavior. Brain Res 886, 113–164 (2000)
- The medial hypothalamic defensive system: hodological organization and functional implications. Pharmacol. Biochem. Behav. 71, 481–491 (2002)
- Wired for reproduction: organization and development of sexually dimorphic circuits in the mammalian forebrain. Annu. Rev. Neurosci. 25, 507–536 (2002)
- Dissecting the brain’s fear system reveals the hypothalamus is critical for responding in subordinate conspecific intruders. Proc. Natl Acad. Sci. USA 106, 4870–4875 (2009) et al.
- Mating and agonistic behavior produce different patterns of Fos immunolabeling in the male Syrian hamster brain. Neuroscience 66, 721–736 (1995) &
- The medial extended amygdala in male reproductive behavior. A node in the mammalian social behavior network. Ann. NY Acad. Sci. 877, 242–257 (1999)
- Do similar neural systems subserve aggressive and sexual behaviour in male rats? Insights from c-Fos and pharmacological studies. Eur. J. Pharmacol. 526, 226–239 (2005) et al.
- Mapping patterns of c-fos expression in the central nervous system after seizure. Science 237, 192–197 (1987) , , &
- Ethoexperimental approaches to the biology of emotion. Annu. Rev. Psychol. 39, 43–68 (1988) &
- Neural connections of the anterior hypothalamus and agonistic behavior in golden hamsters. Brain Behav. Evol. 55, 53–76 (2000) , &
- Vasopressin receptor blockade in the anterior hypothalamus suppresses aggression in hamsters. Physiol. Behav. 44, 235–239 (1988) &
- Neural mechanisms of aggression. Natl. Rev. 8, 536–546 (2007) &
- Imaging neural activity with temporal and cellular resolution using FISH. Curr. Opin. Neurobiol. 11, 579–584 (2001) , , &
- Environment-specific expression of the immediate-early gene Arc in hippocampal neuronal ensembles. Nature Neurosci. 2, 1120–1124 (1999) , , &
- Switching on and off fear by distinct neuronal circuits. Nature 454, 600–606 (2008) et al.
- Efferent connections of the hypothalamic “aggression area” in the rat. Neuroscience 59, 1001–1024 (1994) et al.
- Millisecond-timescale, genetically targeted optical control of neural activity. Nature Neurosci. 8, 1263–1268 (2005) , , , &
- Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry. Nature 466, 622–626 (2010) et al.
- An optical neural interface: in vivo control of rodent motor cortex with integrated fiberoptic and optogenetic technology. J. Neural Eng. 4, S143–S156 (2007) et al.
- Reversible silencing of neuronal excitability in behaving mice by a genetically targeted, ivermectin-gated Cl− channel. Neuron 54, 35–49 (2007) et al.
- Comparative analysis of adeno-associated viral vector serotypes 1, 2, 5, 7, and 8 in mouse brain. Hum. Gene Ther. 18, 195–206 (2007) et al.
- Hypothalamic substrates for brain stimulation-induced patterns of locomotion and escape jumps in the rat. Brain Res. 449, 294–310 (1988) , , &
- Ventromedial hypothalamus and aggressive behavior in rats. Aggress. Behav. 3, 47–56 (1977)
- Behaviour changes in mice following electrolytic lesions in the median hypothalamus. Brain Res. 65, 521–524 (1974) &
- The effect of neurokinin1 receptor blockade on territorial aggression and in a model of violent aggression. Biol. Psychiatry 63, 271–278 (2008) et al.
- Substance P neurotransmission and violent aggression: the role of tachykinin NK(1) receptors in the hypothalamic attack area. Eur. J. Pharmacol. 611, 35–43 (2009) et al.
- Selective electrical silencing of mammalian neurons in vitro by the use of invertebrate ligand-gated chloride channels. J. Neurosci. 22, 7373–7379 (2002) , , , &
- Selective elimination of glutamate activation and introduction of fluorescent proteins into a Caenorhabditis elegans chloride channel. FEBS Lett. 528, 77–82 (2002) , &
- A locked, non-rotating, completely embedded, moveable electrode for chronic brain stimulation studies in freely moving, fighting rats. Physiol. Behav. 31, 259–263 (1983) et al.
- Problems in the study of rodent aggression. Horm. Behav. 44, 161–170 (2003) , &
- Sensory, hormonal, and neural control of maternal aggression in laboratory rodents. Neurosci. Biobehav. Rev. 26, 869–888 (2002) &
- Comparison of aggressive behaviour induced by electrical stimulation in the hypothalamus of male and female rats. Prog. Brain Res. 61, 303–314 (1984) et al.
- Facilitation of the lordosis reflex of female rats from the ventromedial nucleus of the hypothalamus. J. Physiol. (Lond.) 288, 189–202 (1979) &
- Deficit in the lordosis reflex of female rats caused by lesions in the ventromedial nucleus of the hypothalamus. J. Physiol. (Lond.) 288, 203–210 (1979) &
- Combinatorial amygdalar inputs to hippocampal domains and hypothalamic behavior systems. Brain Res. Rev. 38, 247–289 (2001) , &
- Neural correlates of competing fear behaviors evoked by an innately aversive stimulus. J. Neurosci. 23, 3855–3868 (2003) , , &
- Multiple site silicon-based probes for chronic recordings in freely moving rats: implantation, recording and histological verification. J. Neurosci. Methods 98, 77–82 (2000) et al.
- Optical deconstruction of parkinsonian neural circuitry. Science 324, 354–359 (2009) , , , &
- Intrabody gene therapy ameliorates motor, cognitive, and neuropathological symptoms in multiple mouse models of Huntington's disease. J. Neurosci. 29, 13589–13602 (2009) , &
- Supplementary Information (2.8M)
The file contains Supplementary Figures 1-19 with legends, Supplementary Methods, Supplementary Footnotes 1-4 and additional references.
- Supplementary Movie 1 (10.7M)
The sound in this movie corresponds to the response of a neuron recorded from a C57BL/6 male during investigation and attack of a BALB/c male. Viewers are kindly requested not to upload this movie to other publicly accessible sites.
- Supplementary Movie 2 (12.8M)
The sound in this movie corresponds to the response of the same neuron shown in Supplementary Movie 1 during investigation and mounting of a C57BL/6 female. Viewers are kindly requested not to upload this movie to other publicly accessible sites.
- Supplementary Movie 3 (9.5M)
The movie shows an attack towards a BALB/c female is induced by light stimulation of a C57BL/6 male mouse in the VMHvl region. Viewers are kindly requested not to upload this movie to other publicly accessible sites.
- Supplementary Movie 4 (9.2M)
The movie shows an attack towards a glove, which is induced by stimulating VMHvl in a C57BL/6 male mouse. Viewers are kindly requested not to upload this movie to other publicly accessible sites.