Brain-wide genetic mapping identifies the indusium griseum as a prenatal target of pharmacologically unrelated psychostimulants

Proc Natl Acad Sci U S A. 2019 Dec 17;116(51):25958-25967. doi: 10.1073/pnas.1904006116. Epub 2019 Dec 3.

Abstract

Psychostimulant use is an ever-increasing socioeconomic burden, including a dramatic rise during pregnancy. Nevertheless, brain-wide effects of psychostimulant exposure are incompletely understood. Here, we performed Fos-CreERT2-based activity mapping, correlated for pregnant mouse dams and their fetuses with amphetamine, nicotine, and caffeine applied acutely during midgestation. While light-sheet microscopy-assisted intact tissue imaging revealed drug- and age-specific neuronal activation, the indusium griseum (IG) appeared indiscriminately affected. By using GAD67gfp/+ mice we subdivided the IG into a dorsolateral domain populated by γ-aminobutyric acidergic interneurons and a ventromedial segment containing glutamatergic neurons, many showing drug-induced activation and sequentially expressing Pou3f3/Brn1 and secretagogin (Scgn) during differentiation. We then combined Patch-seq and circuit mapping to show that the ventromedial IG is a quasi-continuum of glutamatergic neurons (IG-Vglut1 +) reminiscent of dentate granule cells in both rodents and humans, whose dendrites emanate perpendicularly toward while their axons course parallel with the superior longitudinal fissure. IG-Vglut1 + neurons receive VGLUT1+ and VGLUT2+ excitatory afferents that topologically segregate along their somatodendritic axis. In turn, their efferents terminate in the olfactory bulb, thus being integral to a multisynaptic circuit that could feed information antiparallel to the olfactory-cortical pathway. In IG-Vglut1 + neurons, prenatal psychostimulant exposure delayed the onset of Scgn expression. Genetic ablation of Scgn was then found to sensitize adult mice toward methamphetamine-induced epilepsy. Overall, our study identifies brain-wide targets of the most common psychostimulants, among which Scgn +/Vglut1 + neurons of the IG link limbic and olfactory circuits.

Keywords: Patch-seq; amphetamine; caffeine; human; nicotine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / metabolism
  • Brain / diagnostic imaging
  • Brain / metabolism*
  • Brain Mapping*
  • Dendrites / metabolism
  • Female
  • Gene Expression Regulation*
  • Glutamate Decarboxylase / genetics
  • Humans
  • Interneurons / metabolism
  • Limbic Lobe / anatomy & histology
  • Limbic Lobe / drug effects
  • Limbic Lobe / metabolism*
  • Mice
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neurons / metabolism
  • Olfactory Bulb / metabolism
  • POU Domain Factors / genetics
  • POU Domain Factors / metabolism
  • Secretagogins / genetics
  • Secretagogins / metabolism
  • Vesicular Glutamate Transport Protein 1 / genetics
  • Vesicular Glutamate Transport Protein 1 / metabolism
  • Vesicular Glutamate Transport Protein 2 / genetics
  • Vesicular Glutamate Transport Protein 2 / metabolism
  • gamma-Aminobutyric Acid / metabolism

Substances

  • Nerve Tissue Proteins
  • POU Domain Factors
  • SCGN protein, mouse
  • Secretagogins
  • Slc17a6 protein, mouse
  • Slc17a7 protein, mouse
  • Vesicular Glutamate Transport Protein 1
  • Vesicular Glutamate Transport Protein 2
  • Pou3f3 protein, mouse
  • gamma-Aminobutyric Acid
  • Glutamate Decarboxylase
  • glutamate decarboxylase 1