A retinoraphe projection regulates serotonergic activity and looming-evoked defensive behaviour

Animals promote their survival by avoiding rapidly approaching objects that indicate threats. In mice, looming-evoked defensive responses are triggered by the superior colliculus (SC) which receives direct retinal inputs. However, the specific neural circuits that begin in the retina and mediate this important behaviour remain unclear. Here we identify a subset of retinal ganglion cells (RGCs) that controls mouse looming-evoked defensive responses through axonal collaterals to the dorsal raphe nucleus (DRN) and SC. Looming signals transmitted by DRN-projecting RGCs activate DRN GABAergic neurons that in turn inhibit serotoninergic neurons. Moreover, activation of DRN serotoninergic neurons reduces looming-evoked defensive behaviours. Thus, a dedicated population of RGCs signals rapidly approaching visual threats and their input to the DRN controls a serotonergic self-gating mechanism that regulates innate defensive responses. Our study provides new insights into how the DRN and SC work in concert to extract and translate visual threats into defensive behavioural responses.

[1]  W. Mandemakers,et al.  A Novel Purification Method for CNS Projection Neurons Leads to the Identification of Brain Vascular Cells as a Source of Trophic Support for Corticospinal Motor Neurons , 2008, The Journal of Neuroscience.

[2]  F. Graeff,et al.  Dual role of 5-HT in defense and anxiety , 1997, Neuroscience & Biobehavioral Reviews.

[3]  J. Neumaier,et al.  Serotonin 1B Autoreceptors Originating in the Caudal Dorsal Raphe Nucleus Reduce Expression of Fear and Depression-Like Behavior , 2011, Biological Psychiatry.

[4]  F. Graeff,et al.  Executive and modulatory neural circuits of defensive reactions: Implications for panic disorder , 2014, Neuroscience & Biobehavioral Reviews.

[5]  Picaud Serge,et al.  The optomotor response: A robust first-line visual screening method for mice , 2005, Vision Research.

[6]  Stella F. Lourenco,et al.  Threat modulates perception of looming visual stimuli , 2012, Current Biology.

[7]  Qian Wang,et al.  A parvalbumin-positive excitatory visual pathway to trigger fear responses in mice , 2015, Science.

[8]  Xintian Hu,et al.  Corrigendum: Processing of visually evoked innate fear by a non-canonical thalamic pathway , 2015, Nature Communications.

[9]  Herwig Baier,et al.  A Visual Pathway for Looming-Evoked Escape in Larval Zebrafish , 2015, Current Biology.

[10]  Asif A Ghazanfar,et al.  Multisensory Integration of Looming Signals by Rhesus Monkeys , 2004, Neuron.

[11]  Liqun Luo,et al.  Presynaptic Partners of Dorsal Raphe Serotonergic and GABAergic Neurons , 2014, Neuron.

[12]  Yu Ohmura,et al.  Effects of serotonergic terminal lesion in the amygdala on conditioned fear and innate fear in rats. , 2012, European journal of pharmacology.

[13]  W. Lencer,et al.  Transcytosis of cholera toxin subunits across model human intestinal epithelia. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[14]  Kwok-Fai So,et al.  Y-Like Retinal Ganglion Cells Innervate the Dorsal Raphe Nucleus in the Mongolian Gerbil (Meriones unguiculatus) , 2011, PloS one.

[15]  M. Soiza-Reilly,et al.  Quantitative analysis of glutamatergic innervation of the mouse dorsal raphe nucleus using array tomography , 2011, The Journal of comparative neurology.

[16]  P. Celada,et al.  Control of Dorsal Raphe Serotonergic Neurons by the Medial Prefrontal Cortex: Involvement of Serotonin-1A, GABAA, and Glutamate Receptors , 2001, The Journal of Neuroscience.

[17]  M. Meister,et al.  Rapid Innate Defensive Responses of Mice to Looming Visual Stimuli , 2013, Current Biology.

[18]  W. Ball,et al.  Infant Responses to Impending Collision: Optical and Real , 1971, Science.

[19]  Qingchun Guo,et al.  Serotonin neurons in the dorsal raphe nucleus encode reward signals , 2016, Nature Communications.

[20]  B. Waterhouse,et al.  Retrograde study of hypocretin-1 (orexin-A) projections to subdivisions of the dorsal raphe nucleus in the rat , 2005, Brain Research.

[21]  Minmin Luo,et al.  Dorsal Raphe Neurons Signal Reward through 5-HT and Glutamate , 2014, Neuron.

[22]  Fair M. Vassoler,et al.  Raphe GABAergic Neurons Mediate the Acquisition of Avoidance after Social Defeat , 2013, The Journal of Neuroscience.

[23]  Ian R. Wickersham,et al.  Monosynaptic Restriction of Transsynaptic Tracing from Single, Genetically Targeted Neurons , 2007, Neuron.

[24]  Timothy W. Dunn,et al.  Neural Circuits Underlying Visually Evoked Escapes in Larval Zebrafish , 2016, Neuron.

[25]  Jac Billington,et al.  Neural processing of imminent collision in humans , 2011, Proceedings of the Royal Society B: Biological Sciences.

[26]  D. Tomsic.  Visual motion processing subserving behavior in crabs , 2016, Current Opinion in Neurobiology.

[27]  Onkar S. Dhande,et al.  Contributions of Retinal Ganglion Cells to Subcortical Visual Processing and Behaviors. , 2015, Annual review of vision science.

[28]  A. Bonci,et al.  Serotonergic versus nonserotonergic dorsal raphe projection neurons: differential participation in reward circuitry. , 2014, Cell reports.

[29]  L. P. Morin,et al.  Retinofugal projections in the mouse , 2014, The Journal of comparative neurology.

[30]  H. Nakagawa,et al.  Collision-sensitive neurons in the optic tectum of the bullfrog, Rana catesbeiana. , 2006, Journal of neurophysiology.

[31]  A. Mørk,et al.  The effects of acute treatment with escitalopram on the different stages of contextual fear conditioning are reversed by atomoxetine , 2010, Psychopharmacology.

[32]  G. Laurent,et al.  Elementary Computation of Object Approach by a Wide-Field Visual Neuron , 1995, Science.

[33]  Kwok-Fai So,et al.  Direct Retino-Raphe Projection Alters Serotonergic Tone and Affective Behavior , 2013, Neuropsychopharmacology.

[34]  B. Frost,et al.  Computation of different optical variables of looming objects in pigeon nucleus rotundus neurons , 1998, Nature Neuroscience.

[35]  Martin Y. Peek,et al.  Comparative approaches to escape , 2016, Current Opinion in Neurobiology.

[36]  Edward M. Callaway,et al.  A dedicated circuit linking direction selective retinal ganglion cells to primary visual cortex , 2014, Nature.

[37]  Yong-Jun Liu,et al.  Neuronal Responses to Looming Objects in the Superior Colliculus of the Cat , 2011, Brain, Behavior and Evolution.

[38]  G. E. Pickard,et al.  Dorsal raphe nucleus projecting retinal ganglion cells: Why Y cells? , 2015, Neuroscience & Biobehavioral Reviews.

[39]  L. P. Morin,et al.  The ascending serotonergic system in the hamster: comparison with projections of the dorsal and median raphe nuclei , 1999, Neuroscience.

[40]  H. Dringenberg,et al.  Orienting and defensive behaviors elicited by superior colliculus stimulation in rats: effects of 5-HT depletion, uptake inhibition, and direct midbrain or frontal cortex application , 2003, Behavioural Brain Research.

[41]  B. Roth,et al.  Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand , 2007, Proceedings of the National Academy of Sciences.

[42]  M. Nicolelis,et al.  Remote Control of Neuronal Activity in Transgenic Mice Expressing Evolved G Protein-Coupled Receptors , 2009, Neuron.

[43]  G Chouvet,et al.  Role and Origin of the GABAergic Innervation of Dorsal Raphe Serotonergic Neurons , 2000, The Journal of Neuroscience.

[44]  G. Aston-Jones,et al.  Evidence that cholera toxin B subunit (CTb) can be avidly taken up and transported by fibers of passage , 1995, Brain Research.

[45]  N. Canteras,et al.  The many paths to fear , 2012, Nature Reviews Neuroscience.

[46]  Shurong Wang,et al.  Tectal neurons signal impending collision of looming objects in the pigeon , 2005, The European journal of neuroscience.

[47]  Edward M. Callaway,et al.  A dedicated circuit links direction-selective retinal ganglion cells to the primary visual cortex , 2014 .

[48]  S. Sherman,et al.  Morphology of physiologically identified retinal X and Y axons in the cat's thalamus and midbrain as revealed by intraaxonal injection of biocytin , 1995, The Journal of comparative neurology.

[49]  James A. Caviness,et al.  Persistent Fear Responses in Rhesus Monkeys to the Optical Stimulus of "Looming" , 1962, Science.

[50]  J. King,et al.  The role of 5-HT1A receptors in the behavioral responses associated with innate fear. , 2008, Behavioral neuroscience.

[51]  Xiaobai Li,et al.  5-HT1A receptor agonist affects fear conditioning through stimulations of the postsynaptic 5-HT1A receptors in the hippocampus and amygdala. , 2006, European journal of pharmacology.

[52]  G. Silberberg,et al.  A Whole-Brain Atlas of Inputs to Serotonergic Neurons of the Dorsal and Median Raphe Nuclei , 2014, Neuron.

[53]  Matthias Bethge,et al.  The functional diversity of retinal ganglion cells in the mouse , 2015, Nature.

[54]  Li Zhang,et al.  ON and OFF retinal ganglion cells differentially regulate serotonergic and GABAergic activity in the dorsal raphe nucleus , 2016, Scientific Reports.

[55]  Takeshi Izumi,et al.  Selective serotonin reuptake inhibitor reduces conditioned fear through its effect in the amygdala. , 2004, European journal of pharmacology.