Elsevier

Biological Psychiatry

Volume 83, Issue 7, 1 April 2018, Pages 607-617
Biological Psychiatry

Archival Report
Identification of a Corticohabenular Circuit Regulating Socially Directed Behavior

https://doi.org/10.1016/j.biopsych.2017.10.032Get rights and content

Abstract

Background

The prefrontal cortex (PFC) has been implicated in the pathophysiology of social dysfunction, but the specific circuit partners mediating PFC function in health and disease are unclear.

Methods

The excitatory designer receptor exclusively activated by designer drugs (DREADD) hM3Dq was used to induce PFC activation during social behavior measured in the three-chamber sociability assay (rats/mice). Functional magnetic resonance imaging was combined with hM3Dq-mediated PFC activation to identify novel nodes in the “social brain” in a hypothesis-free manner. In multiplexed DREADD experiments, hM3Dq and the inhibitory KORDi were used to bidirectionally modulate PFC activity and measure social behavior and global functional magnetic resonance imaging signature. To characterize the functional role of specific nodes identified in this functional magnetic resonance imaging screen, we used anterograde and retrograde tracers, optogenetic and DREADD-assisted circuit mapping, and circuit behavioral experiments.

Results

PFC activation suppressed social behavior and modulated activity in a number of regions involved in emotional behavior. Bidirectional modulation of PFC activity further refined this subset of brain regions and identified the habenula as a node robustly correlated with PFC activity. Furthermore, we showed that the lateral habenula (LHb) receives direct synaptic input from the PFC and that activation of LHb neurons or the PFC inputs to the LHb suppresses social preference. Finally, we demonstrated that LHb inhibition can prevent the social deficits induced by PFC activation.

Conclusions

The LHb is thought to provide reward-related contextual information to the mesolimbic reward system known to be involved in social behavior. Thus, PFC projections to the LHb may represent an important part of descending PFC pathways that control social behavior.

Section snippets

Methods and Materials

Detailed protocols can be found in the Supplement.

Global Functional MRI Signature Associated With Social Dysfunction

To screen for global activity changes associated with PFC hyperactivity and social dysfunction, we took advantage of DREADDs 16, 17, 18. DREADDs are engineered G protein–coupled receptors designed to respond to an otherwise biologically inert ligand. To increase excitation in the PFC, we transduced PFC pyramidal neurons (Emx-positive) with the excitatory DREADD hM3Dq. Using multielectrode arrays, we confirmed that DREADDs led to a persistent and strong increase in neuronal activity. Brain

Discussion

Perturbed circuit homeostasis in the PFC has been proposed as a common neural substrate of social impairments seen in ASD and schizophrenia. Rodent optogenetic studies have shown that the PFC governs social behavior via top-down control over the activity dynamics of the midbrain reward system 31, 32. However, the neural pathways that connect the PFC to the social reward pathways have not yet been delineated. Here we screened for PFC circuit partners involved in the control of social behavior

Acknowledgments and Disclosures

This work is partially supported by the Gatsby Charitable Trust (AG) and by the postdoctoral program at F. Hoffman–La Roche (MB, TJS).

We thank Bryan L. Roth for the DREADD constructs. We thank Claire Coulon-Bainier for help with surgical procedures and thank Stephanie Schoeppenthau, Sebastian Debilly, and Ciril Marius Waelti for technical assistance with the fMRI experiments. We thank Roger Redondo for help with the in vivo optogenetic experiments. We also thank Laurence Ozmen, Marie-Therese

References (44)

  • T.C. Jhou et al.

    The rostromedial tegmental nucleus (RMTg), a major GABAergic afferent to midbrain dopamine neurons, selectively encodes aversive stimuli and promotes behavioral inhibition

    Neuron

    (2009)
  • R. van Zessen et al.

    Activation of VTA GABA neurons disrupts reward consumption

    Neuron

    (2012)
  • A.A. Curley et al.

    Cortical deficits of glutamic acid decarboxylase 67 expression in schizophrenia: Clinical, protein, and cell type-specific features

    Am J Psychiatry

    (2011)
  • G.S. Dichter et al.

    Autism is characterized by dorsal anterior cingulate hyperactivation during social target detection

    Soc Cogn Affect Neurosci

    (2009)
  • J.D. Lewine et al.

    Magnetoencephalographic patterns of epileptiform activity in children with regressive autism spectrum disorders

    Pediatrics

    (1999)
  • C. Gillberg et al.

    Autism and Asperger syndrome: Coexistence with other clinical disorders

    Acta Psychiatr Scand

    (2000)
  • I. Voineagu et al.

    Transcriptomic analysis of autistic brain reveals convergent molecular pathology

    Nature

    (2011)
  • J.L.R. Rubenstein et al.

    Model of autism: Increased ratio of excitation/inhibition in key neural systems

    Genes Brain Behav

    (2003)
  • O. Yizhar et al.

    Neocortical excitation/inhibition balance in information processing and social dysfunction

    Nature

    (2011)
  • S. Lammel et al.

    Input-specific control of reward and aversion in the ventral tegmental area

    Nature

    (2012)
  • M. Matsumoto et al.

    Lateral habenula as a source of negative reward signals in dopamine neurons

    Nature

    (2007)
  • M. Matsumoto et al.

    Representation of negative motivational value in the primate lateral habenula

    Nat Neurosci

    (2009)
  • Cited by (68)

    View all citing articles on Scopus

    AG is currently affiliated with Research and Early Development, Biogen, Cambridge, Massachusetts.

    View full text