Disrupted Prefrontal Regulation of Striatal Subjective Value Signals in Psychopathy

July 5, 2017

Psychopathy is a personality disorder with strong links to criminal behavior. While research on psychopathy has focused largely on socio-affective dysfunction, recent data suggest that aberrant decision making may also play an important role. Yet, the circuit-level mechanisms underlying maladaptive decision making in psychopathy remain unclear. Here, we used a multi-modality functional imaging approach to identify these mechanisms in a population of adult male incarcerated offenders. Psychopathy was associated with stronger subjective value-related activity within the nucleus accumbens (NAcc) during inter-temporal choice and with weaker intrinsic functional connectivity between NAcc and ventromedial prefrontal cortex (vmPFC). NAcc-vmPFC connectivity strength was negatively correlated with NAcc subjective value-related activity; however, this putative regulatory pattern was abolished as psychopathy severity increased. Finally, weaker cortico-striatal regulation predicted more frequent criminal convictions. These data suggest that cortico-striatal circuit dysregulation drives maladaptive decision making in psychopathy, supporting the notion that reward system dysfunction comprises an important neurobiological risk factor.


Ctip1 Controls Acquisition of Sensory Area Identity and Establishment of Sensory Input Fields in the Developing Neocortex

June 29, 2017

Abstract: While transcriptional controls over the size and relative position of cortical areas have been identified, less is known about regulators that direct acquisition of area-specific characteristics. Here, we report that the transcription factor Ctip1 functions in primary sensory areas to repress motor and activate sensory programs of gene expression, enabling establishment of sharp molecular boundaries defining functional areas. In Ctip1 mutants, abnormal gene expression leads to aberrantly motorized corticocortical and corticofugal output connectivity. Ctip1 critically regulates differentiation of layer IV neurons, and selective loss of Ctip1 in cortex deprives thalamocortical axons of their receptive "sensory field" in layer IV, which normally provides a tangentially and radially defined compartment of dedicated synaptic territory. Therefore, although thalamocortical axons invade appropriate cortical regions, they are unable to organize into properly configured sensory maps. Together, these data identify Ctip1 as a critical control over sensory area development.


Cited2 Regulates Neocortical Layer II/III Generation and Somatosensory Callosal Projection Neuron Development and Connectivity

June 15, 2017

Fame RM, MacDonald JL, Dunwoodie SL, Takahashi E, Macklis JD

The neocortex contains hundreds to thousands of distinct subtypes of precisely connected neurons, allowing it to perform remarkably complex tasks of high-level cognition. Callosal projection neurons (CPN) connect the cerebral hemispheres via the corpus callosum, integrating cortical information and playing key roles in associative cognition. CPN are a strikingly diverse set of neuronal subpopulations, and development of this diversity requires precise control by a complex, interactive set of molecular effectors. We have found that the transcriptional coregulator Cited2 regulates and refines two stages of CPN development. Cited2 is expressed broadly by progenitors in the embryonic day 15.5 subventricular zone, during the peak of superficial layer CPN birth, with a progressive postmitotic refinement in expression, becoming restricted to CPN of the somatosensory cortex postnatally. We generated progenitor-stage and postmitotic forebrain-specific Cited2 conditional knock-out mice, using the Emx1-Cre and NEX-Cre mouse lines, respectively. We demonstrate that Cited2 functions in progenitors, but is not necessary postmitotically, to regulate both (1) broad generation of layer II/III CPN and (2) acquisition of precise area-specific molecular identity and axonal/dendritic connectivity of somatosensory CPN. This novel CPN subtype-specific and area-specific control from progenitor action of Cited2 adds yet another layer of complexity to the multistage developmental regulation of neocortical development.

This study identifies Cited2 as a novel subtype-specific and area-specific control over development of distinct subpopulations within the broad population of callosal projection neurons (CPN), whose axons connect the two cerebral hemispheres via the corpus callosum (CC). Currently, how the remarkable diversity of CPN subtypes is specified, and how they differentiate to form highly precise and specific circuits, are largely unknown. We found that Cited2 functions within subventricular zone progenitors to both broadly regulate generation of superficial layer CPN throughout the neocortex, and to refine precise area-specific development and connectivity of somatosensory CPN. Gaining insight into molecular development and heterogeneity of CPN will advance understanding of both diverse functions of CPN and of the remarkable range of neurodevelopmental deficits correlated with CPN/CC development

Whole-brain serial-section electron microscopy in larval zebrafish

May 18, 2017

Hildebrand DGC, Cicconet M, Torres RM, Choi W, Quan TM, Moon J, Wetzel AW, Scott Champion A, Graham BJ, Randlett O, Plummer GS, Portugues R, Bianco IH, Saalfeld S, Baden AD, Lillaney K, Burns R, Vogelstein JT, Schier AF, Lee WA, Jeong WK, Lichtman JW, Engert F.

High-resolution serial-section electron microscopy (ssEM) makes it possible to investigate the dense meshwork of axons, dendrites, and synapses that form neuronal circuits. However, the imaging scale required to comprehensively reconstruct these structures is more than ten orders of magnitude smaller than the spatial extents occupied by networks of interconnected neurons, some of which span nearly the entire brain. Difficulties in generating and handling data for large volumes at nanoscale resolution have thus restricted vertebrate studies to fragments of circuits. These efforts were recently transformed by advances in computing, sample handling, and imaging techniques, but high-resolution examination of entire brains remains a challenge. Here, we present ssEM data for the complete brain of a larval zebrafish (Daniorerio) at 5.5 days post-fertilization. Our approach utilizes multiple rounds of targeted imaging at different scales to reduce acquisition time and data management requirements. The resulting dataset can be analysed to reconstruct neuronal processes, permitting us to survey all myelinated axons (the projectome). These reconstructions enable precise investigations of neuronal morphology, which reveal remarkable bilateral symmetry in myelinated reticulospinal and lateral line afferent axons. We further set the stage for whole-brain structure-function comparisons by co-registering functional reference atlases and in vivo two-photon fluorescence microscopy data from the same specimen. All obtained images and reconstructions are provided as an open-access resource.


Joshua Sanes wins 2017 Gruber Neuroscience Prize

May 17, 2017

May 17, 2017, New Haven, CT - Joshua R. Sanes, PhD, of Harvard University, is the recipient of the 2017 Gruber Neuroscience Prize for his seminal contributions regarding the mechanisms and molecules that drive the formation and specificity of neural connections within the nervous system. His work has fundamentally transformed the study of these connections, known as synapses, and has led to influential new ideas about how the brain processes information. Sanes has also helped to develop innovative technologies for marking and manipulating neurons and the synapses they form.