Wired for behaviors: from development to function of innate limbic system circuitry

The limbic system of the brain regulates a number of behaviors that are essential for the survival of all vertebrate species including humans. The limbic system predominantly controls appropriate responses to stimuli with social, emotional, or motivational salience, which includes innate behaviors such as mating, aggression, and defense. Activation of circuits regulating these innate behaviors begins in the periphery with sensory stimulation (primarily via the olfactory system in rodents), and is then processed in the brain by a set of delineated structures that primarily includes the amygdala and hypothalamus. While the basic neuroanatomy of these connections is well-established, much remains unknown about how information is processed within innate circuits and how genetic hierarchies regulate development and function of these circuits. Utilizing innovative technologies including channel rhodopsin-based circuit manipulation and genetic manipulation in rodents, recent studies have begun to answer these central questions. In this article we review the current understanding of how limbic circuits regulate sexually dimorphic behaviors and how these circuits are established and shaped during pre- and post-natal development. We also discuss how understanding developmental processes of innate circuit formation may inform behavioral alterations observed in neurodevelopmental disorders, such as autism spectrum disorders, which are characterized by limbic system dysfunction

Neonatal NMDA receptor blockade disrupts spike timing and glutamatergic synapses in fast spiking interneurons in a NMDA receptor hypofunction model of schizophrenia

The dysfunction of parvalbumin-positive, fast-spiking interneurons (FSI) is considered a primary contributor to the pathophysiology of schizophrenia (SZ), but deficits in FSI physiology have not been explicitly characterized. We show for the first time, that a widely-employed model of schizophrenia minimizes first spike latency and increases GluN2B-mediated current in neocortical FSIs. The reduction in FSI first-spike latency coincides with reduced expression of the Kv1.1 potassium channel subunit which provides a biophysical explanation for the abnormal spiking behavior. Similarly, the increase in NMDA current coincides with enhanced expression of the GluN2B NMDA receptor subunit, specifically in FSIs. In this study mice were treated with the NMDA receptor antagonist, MK-801, during the first week of life. During adolescence, we detected reduced spike latency and increased GluN2B-mediated NMDA current in FSIs, which suggests transient disruption of NMDA signaling during neonatal development exerts lasting changes in the cellular and synaptic physiology of neocortical FSIs. Overall, we propose these physiological disturbances represent a general impairment to the physiological maturation of FSIs which may contribute to schizophrenia-like behaviors produced by this model

Amygdala Corticofugal Input Shapes Mitral Cell Responses in the Accessory Olfactory Bulb

Interconnections between the olfactory bulb and the amygdala are a major pathway for triggering strong behavioral responses to a variety of odorants. However, while this broad mapping has been established, the patterns of amygdala feedback connectivity and the influence on olfactory circuitry remain unknown. Here, using a combination of neuronal tracing approaches, we dissect the connectivity of a cortical amygdala [posteromedial cortical nucleus (PmCo)] feedback circuit innervating the mouse accessory olfactory bulb. Optogenetic activation of PmCo feedback mainly results in feedforward mitral cell (MC) inhibition through direct excitation of GABAergic granule cells. In addition, LED-driven activity of corticofugal afferents increases the gain of MC responses to olfactory nerve stimulation. Thus, through corticofugal pathways, the PmCo likely regulates primary olfactory and social odor processing

Molecular and behavioral profiling of Dbx1-derived neurons in the arcuate, lateral and ventromedial hypothalamic nuclei.

BACKGROUND: Neurons in the hypothalamus function to regulate the state of the animal during both learned and innate behaviors, and alterations in hypothalamic development may contribute to pathological conditions such as anxiety, depression or obesity. Despite many studies of hypothalamic development and function, the link between embryonic development and innate behaviors remains unexplored. Here, focusing on the embryonically expressed homeodomain-containing gene Developing Brain Homeobox 1 (Dbx1), we explored the relationship between embryonic lineage, post-natal neuronal identity and lineage-specific responses to innate cues. We found that Dbx1 is widely expressed across multiple developing hypothalamic subdomains. Using standard and inducible fate-mapping to trace the Dbx1-derived neurons, we identified their contribution to specific neuronal subtypes across hypothalamic nuclei and further mapped their activation patterns in response to a series of well-defined innate behaviors. RESULTS: Dbx1-derived neurons occupy multiple postnatal hypothalamic nuclei including the lateral hypothalamus (LH), arcuate nucleus (Arc) and the ventral medial hypothalamus (VMH). Within these nuclei, Dbx1 (+) progenitors generate a large proportion of the Pmch-, Nesfatin-, Cart-, Hcrt-, Agrp- and ERα-expressing neuronal populations, and to a lesser extent the Pomc-, TH- and Aromatase-expressing populations. Inducible fate-mapping reveals distinct temporal windows for development of the Dbx1-derived LH and Arc populations, with Agrp(+) and Cart(+) populations in the Arc arising early (E7.5-E9.5), while Pmch(+) and Hcrt(+) populations in the LH derived from progenitors expressing Dbx1 later (E9.5-E11.5). Moreover, as revealed by c-Fos labeling, Dbx1-derived cells in male and female LH, Arc and VMH are responsive during mating and aggression. In contrast, Dbx1-lineage cells in the Arc and LH have a broader behavioral tuning, which includes responding to fasting and predator odor cues. CONCLUSION: We define a novel fate map of the hypothalamus with respect to Dbx1 expression in hypothalamic progenitor zones. We demonstrate that in a temporally regulated manner, Dbx1-derived neurons contribute to molecularly distinct neuronal populations in the LH, Arc and VMH that have been implicated in a variety of hypothalamic-driven behaviors. Consistent with this, Dbx1-derived neurons in the LH, Arc and VMH are activated during stress and other innate behavioral responses, implicating their involvement in these diverse behaviors

Sonic hedgehog expressing and responding cells generate neuronal diversity in the medial amygdala

<p>Abstract</p> <p>Background</p> <p>The mammalian amygdala is composed of two primary functional subdivisions, classified according to whether the major output projection of each nucleus is excitatory or inhibitory. The posterior dorsal and ventral subdivisions of the medial amygdala, which primarily contain inhibitory output neurons, modulate specific aspects of innate socio-sexual and aggressive behaviors. However, the development of the neuronal diversity of this complex and important structure remains to be fully elucidated.</p> <p>Results</p> <p>Using a combination of genetic fate-mapping and loss-of-function analyses, we examined the contribution and function of <it>Sonic hedgehog </it>(<it>Shh</it>)-expressing and <it>Shh</it>-responsive (<it>Nkx2-1</it>⁺and <it>Gli1</it>⁺) neurons in the medial amygdala. Specifically, we found that <it>Shh- </it>and <it>Nkx2-1-</it>lineage cells contribute differentially to the dorsal and ventral subdivisions of the postnatal medial amygdala. These <it>Shh</it>- and <it>Nkx2-1</it>-lineage neurons express overlapping and non-overlapping inhibitory neuronal markers, such as Calbindin, FoxP2, nNOS and Somatostatin, revealing diverse fate contributions in discrete medial amygdala nuclear subdivisions. Electrophysiological analysis of the <it>Shh</it>-derived neurons additionally reveals an important functional diversity within this lineage in the medial amygdala. Moreover, inducible <it>Gli1^CreER(T2)</it>temporal fate mapping shows that early-generated progenitors that respond to <it>Shh </it>signaling also contribute to medial amygdala neuronal diversity. Lastly, analysis of <it>Nkx2-1 </it>mutant mice demonstrates a genetic requirement for <it>Nkx2-1 </it>in inhibitory neuronal specification in the medial amygdala distinct from the requirement for <it>Nkx2-1 </it>in cerebral cortical development.</p> <p>Conclusions</p> <p>Taken together, these data reveal a differential contribution of <it>Shh-</it>expressing and <it>Shh</it>-responding cells to medial amygdala neuronal diversity as well as the function of <it>Nkx2-1 </it>in the development of this important limbic system structure.</p

Specialized care improves outcomes for patients with cirrhosis who require general surgical operations

BACKGROUND: General surgical operations on patients with cirrhosis have historically been associated with high morbidity and mortality rates. This study examines a contemporary series of patients with cirrhosis undergoing general surgical procedures. METHODS: A retrospective evaluation of 358 cirrhotic patients undergoing general surgical operations at a single institution between 2004-2015 was performed. Thirty- and 90-day mortality along with complications and subsequent transplantation rates were examined. RESULTS: 358 cirrhotic patients were identified. The majority were Child-Turcotte-Pugh class (CTP) A (55.9%) followed by class B (32.4%) and class C (11.7%). Mean MELD score differed significantly between the groups (8.7 vs. 12.1 vs. 20.1; p<0.001). The most common operations were herniorrhaphy (29.9%), cholecystectomy (19.3%), and liver resection (14.5%). The majority of cases were performed semi-electively (68.4%), however, within the CTP C patients most cases were performed emergently (73.8%). Thirty and 90-day mortality for all patients were 5% and 6%, respectively. Mortality rates increased from CTP A to CTP C (30 day: 3.0% vs. 5.2% vs. 14.3%; p = 0.01; 90 day: 4.5% vs. 6.9% vs. 16.7%; p = 0.016). Additionally, 30-day mortality (12.8% vs. 2.3%; p<0.001), 90 day mortality (16.0% vs. 3.4%; p<0.001) were higher for emergent compared to elective cases. A total of 13 (3.6%) patients underwent transplantation ≤ 90 days from surgery. No elective cases resulted in an urgent transplantation. CONCLUSION: Performing general surgical operations on cirrhotic patients carries a significant morbidity and mortality. This contemporary series from a specialized liver center demonstrates improved outcomes compared to historical series. These data strongly support early referral of cirrhotic patients needing general surgical operation to centers with liver expertise to minimize morbidity and mortality

Developmental Origin of PreBotzinger Complex Respiratory Neurons

A subset of preBötzinger Complex (preBötC) neurokinin 1 receptor (NK1R) and somatostatin peptide (SST)-expressing neurons are necessary for breathing in adult rats, in vivo. Their developmental origins and relationship to other preBötC glutamatergic neurons are unknown. Here we show, in mice, that the “core” of preBötC SST+/NK1R+/SST 2a receptor+ (SST2aR) neurons, are derived from Dbx1-expressing progenitors. We also show that Dbx1-derived neurons heterogeneously coexpress NK1R and SST2aR within and beyond the borders of preBötC. More striking, we find that nearly all non-catecholaminergic glutamatergic neurons of the ventrolateral medulla (VLM) are also Dbx1 derived. PreBötC SST+ neurons are born between E9.5 and E11.5 in the same proportion as non-SST-expressing neurons. Additionally, preBötC Dbx1 neurons are respiratory modulated and show an early inspiratory phase of firing in rhythmically active slice preparations. Loss of Dbx1 eliminates all glutamatergic neurons from the respiratory VLM including preBötC NK1R+/SST+ neurons. Dbx1 mutant mice do not express any spontaneous respiratory behaviors in vivo. Moreover, they do not generate rhythmic inspiratory activity in isolated en bloc preparations even after acidic or serotonergic stimulation. These data indicate that preBötC core neurons represent a subset of a larger, more heterogeneous population of VLM Dbx1-derived neurons. These data indicate that Dbx1-derived neurons are essential for the expression and, we hypothesize, are responsible for the generation of respiratory behavior both in vitro and in vivo

Pax6 Is Required at the Telencephalic Pallial-Subpallial Boundary for the Generation of Neuronal Diversity in the Postnatal Limbic System

During embryogenesis, the pallial-subpallial boundary (PSB) divides the two main progenitor domains in the telencephalon: the pallium, the major source of excitatory neurons, and the subpallium, the major source of inhibitory neurons. The PSB is formed at the molecular interface between the pallial (high Pax6+) and subpallial (high Gsx2+) ventricular zone (VZ) compartments. Initially, the PSB contains cells that express both Pax6 and Gsx2, but during later stages of development this boundary is largely refined into two separate compartments. In this study we examined the developmental mechanisms underlying PSB boundary formation and the postnatal consequences of conditional loss of Pax6 function at the PSB on neuronal fate in the amygdala and olfactory bulb, two targets of PSB-derived migratory populations. Our cell fate and time-lapse imaging analyses reveal that the sorting of Pax6+ and Gsx2+ progenitors during embryogenesis is the result of a combination of changes in gene expression and cell movements. Interestingly, we find that in addition to giving rise to inhibitory neurons in the amygdala and olfactory bulb, Gsx2+ progenitors generate a subpopulation of amygdala excitatory neurons. Consistent with this finding, targeted conditional ablation of Pax6 in Gsx2+ progenitors results in discrete local embryonic patterning defects that are linked to changes in the generation of subsets of postnatal excitatory and inhibitory neurons in the amygdala and inhibitory neurons in the olfactory bulb. Thus, in PSB progenitors, Pax6 plays an important role in the generation of multiple subtypes of neurons that contribute to the amygdala and olfactory bulb

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin