Catecholamines, such as dopamine, are evolutionarily ancient neurotransmitters that play an essential role in mediating behavior. In vertebrates, dopamine is central to the nigrostriatal motor and mesolimbic reward systems. Despite its importance, the distribution of the dopaminergic system has not been well studied in the teleost brain. The African cichlid fish Astatotilapia burtoni has become an important model system in social neuroscience and lends itself to uncovering how social decisions are implemented in the brain. To understand better where dopamine acts to regulate social behavior in this species, we have determined the distribution of putative dopaminergic cells and fibers (by tyrosine hydroxylase immunohistochemistry) and dopamine receptors (by in situ hybridization for the D(1A) and D(2) dopamine receptor subtypes) throughout the forebrain and part of the mesencephalon of A. burtoni. Tyrosine hydroxylase immunoreactivity was evident in several regions of the fore- and midbrain, in support of putative homologies to tetrapods. Additionally, the D(1A) and D(2) receptors were identified in brain regions known to modulate social behavior in other vertebrates, including the proposed teleost homologues of the mammalian amygdalar complex, hippocampus, striatum, preoptic area, anterior hypothalamus, ventromedial hypothalamus, and ventral tegmental area/substantia nigra pars compacta. Tyrosine hydroxylase-immunoreactive fibers as well as D(1A) and D(2) receptor expression overlap almost completely in their distribution. These results significantly extend our understanding of the distribution of the dopaminergic system in the teleost brain and suggest a conserved role of dopamine in modulating behavior across vertebrates.

Across vertebrates, the mesolimbic reward system is a highly conserved neural network that serves to evaluate the salience of environmental stimuli, with dopamine as the neurotransmitter most relevant to its function. Although brain regions in the dopaminergic reward system have been well characterized in mammals, homologizing these brain areas with structures in teleosts has been controversial, especially for the mesencephalo-diencephalic dopaminergic cell populations. Here we examine the neurochemical profile of five dopaminergic cell groups (Vc, POA, PPr, TPp, pTn) in the model cichlid Astatotilapia burtoni to better understand putative homology relationships between teleosts and mammals. We characterized in the adult brain the expression patterns of three genes (etv5, nr4a2, and pitx3) that either specify dopaminergic cell fate or maintain dopaminergic cell populations. We then determined whether these genes are expressed in dopaminergic cells. We find many striking similarities in these gene expression profiles between dopaminergic cell populations in teleosts and their putative mammalian homologs. Our results suggest that many of these dopaminergic cell groups are indeed evolutionarily ancient and conserved across vertebrates.

In humans, brain oscillations support critical features of memory formation. However, understanding the molecular mechanisms underlying this activity remains a major challenge. Here, we measured memory-sensitive oscillations using intracranial electroencephalography recordings from the temporal cortex of patients performing an episodic memory task. When these patients subsequently underwent resection, we employed transcriptomics on the temporal cortex to link gene expression with brain oscillations and identified genes correlated with oscillatory signatures of memory formation across six frequency bands. A co-expression analysis isolated oscillatory signature-specific modules associated with neuropsychiatric disorders and ion channel activity, with highly correlated genes exhibiting strong connectivity within these modules. Using single-nucleus transcriptomics, we further revealed that these modules are enriched for specific classes of both excitatory and inhibitory neurons, and immunohistochemistry confirmed expression of highly correlated genes. This unprecedented dataset of patient-specific brain oscillations coupled to genomics unlocks new insights into the genetic mechanisms that support memory encoding.

Repeated cocaine exposure causes persistent, maladaptive alterations in brain and behavior, and hope for effective therapeutics lies in understanding these processes. We describe here an essential role for fragile X mental retardation protein (FMRP), an RNA-binding protein and regulator of dendritic protein synthesis, in cocaine conditioned place preference, behavioral sensitization, and motor stereotypy. Cocaine reward deficits in FMRP-deficient mice stem from elevated mGluR5 (or GRM5) function, similar to a subset of fragile X symptoms, and do not extend to natural reward. We find that FMRP functions in the adult nucleus accumbens (NAc), a critical addiction-related brain region, to mediate behavioral sensitization but not cocaine reward. FMRP-deficient mice also exhibit several abnormalities in NAc medium spiny neurons, including reduced presynaptic function and premature changes in dendritic morphology and glutamatergic neurotransmission following repeated cocaine treatment. Together, our findings reveal FMRP as a critical mediator of cocaine-induced behavioral and synaptic plasticity.