Inhibitory Input from the Lateral Hypothalamus to the Ventral Tegmental Area Disinhibits Dopamine Neurons and Promotes Behavioral Activation

Projections from the lateral hypothalamus (LH) to the ventral tegmental area (VTA), containing both GABAergic and glutamatergic components, encode conditioned responses and control compulsive reward-seeking behavior. GABAergic neurons in the LH have been shown to mediate appetitive and feeding-related behaviors. Here we show that the GABAergic component of the LH-VTA pathway supports positive reinforcement and place preference, while the glutamatergic component mediates place avoidance. In addition, our results indicate that photoactivation of these projections modulates other behaviors, such as social interaction and perseverant investigation of a novel object. We provide evidence that photostimulation of the GABAergic LH-VTA component, but not the glutamatergic component, increases dopamine (DA) release in the nucleus accumbens (NAc) via inhibition of local VTA GABAergic neurons. Our study clarifies how GABAergic LH inputs to the VTA can contribute to generalized behavioral activation across multiple contexts, consistent with a role in increasing motivational salience.National Institute of Mental Health (U.S.) (Grant R01-MH102441-01

Decoding Neural Circuits that Control Compulsive Sucrose Seeking

SummaryThe lateral hypothalamic (LH) projection to the ventral tegmental area (VTA) has been linked to reward processing, but the computations within the LH-VTA loop that give rise to specific aspects of behavior have been difficult to isolate. We show that LH-VTA neurons encode the learned action of seeking a reward, independent of reward availability. In contrast, LH neurons downstream of VTA encode reward-predictive cues and unexpected reward omission. We show that inhibiting the LH-VTA pathway reduces “compulsive” sucrose seeking but not food consumption in hungry mice. We reveal that the LH sends excitatory and inhibitory input onto VTA dopamine (DA) and GABA neurons, and that the GABAergic projection drives feeding-related behavior. Our study overlays information about the type, function, and connectivity of LH neurons and identifies a neural circuit that selectively controls compulsive sugar consumption, without preventing feeding necessary for survival, providing a potential target for therapeutic interventions for compulsive-overeating disorder

Nature

The ability to associate temporally segregated information and assign positive or negative valence to environmental cues is paramount for survival. Studies have shown that different basolateral amygdala (BLA) projections are potentiated following reward or punishment learning1–7. However, we do not yet understand how valence specific information is routed to the BLA neurons with the appropriate downstream projections. Nor do we understand how to reconcile the subsecond timescales of synaptic plasticity8–11 with the longer timescales separating the predictive cues from their outcomes. Here, we demonstrate that neurotensin (NT) neurons in the paraventricular nucleus of the thalamus (PVT) projecting to the BLA (PVT-BLA:NT) mediate valence assignment by exerting concentration-dependent modulation in BLA during associative learning. We found that optogenetic activation of the PVT-BLA:NT projection promotes reward learning, while PVT-BLA projection-specific Nt gene knockout augments punishment learning. Using genetically encoded calcium and NT sensors, we further revealed that both calcium dynamics within the PVT-BLA:NT projection and NT concentrations in the BLA are enhanced after reward learning and reduced after punishment learning. Finally, we showed that CRISPR-mediated knockout of the Nt gene in the PVT-BLA pathway blunts BLA neural dynamics and attenuates the preference to active behavioral strategies to reward and punishment predictive cues. Taken together, we have identified NT as a neuropeptide that signals valence in the BLA, and showed that NT is a critical neuromodulator that orchestrates positive and negative valence assignment in amygdala neurons by extending valence-specific plasticity to behaviorally-relevant timescales

The Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia : design, results and future prospects

The impact of many unfavorable childhood traits or diseases, such as low birth weight and mental disorders, is not limited to childhood and adolescence, as they are also associated with poor outcomes in adulthood, such as cardiovascular disease. Insight into the genetic etiology of childhood and adolescent traits and disorders may therefore provide new perspectives, not only on how to improve wellbeing during childhood, but also how to prevent later adverse outcomes. To achieve the sample sizes required for genetic research, the Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia were established. The majority of the participating cohorts are longitudinal population-based samples, but other cohorts with data on early childhood phenotypes are also involved. Cohorts often have a broad focus and collect(ed) data on various somatic and psychiatric traits as well as environmental factors. Genetic variants have been successfully identified for multiple traits, for example, birth weight, atopic dermatitis, childhood BMI, allergic sensitization, and pubertal growth. Furthermore, the results have shown that genetic factors also partly underlie the association with adult traits. As sample sizes are still increasing, it is expected that future analyses will identify additional variants. This, in combination with the development of innovative statistical methods, will provide detailed insight on the mechanisms underlying the transition from childhood to adult disorders. Both consortia welcome new collaborations. Policies and contact details are available from the corresponding authors of this manuscript and/or the consortium websites.Peer reviewe

The good and bad of stress: implications for memory and adaptive processes

Stress spedt een steeds grotere rol in onze moderne samenleving. Iedereen is er ooit mee geconfronteerd en moet ermee omgaan. Echter hoeft stress niet noodzakelijk slecht te zi.in. Op de korte termiin kan stress, of de lichamelijke reactie op stress, ons helpen om in tijden van druk beter te presteren en ons cognitieve mogelijkheden te vergroten. Elke situatie beschouwt als stress leidt tot een serie gecoordineerde reacties en resulteert in een verhoogde afgifte van de stresshormonen adrenaline, noradrenaline en glucocorticoiden uit de bijnieren en de hersenen. Al deze hormonen dragen samen bij aan de fysiologische veranderingen die ons gespannen laten voelen en op hetzeltde moment in staat brengen om en eflectief te reageren op een bedreigende situatie en ons help en voorbereid te zijn op toekomstige gebeurtenissen. In hootdstuk I van dit proefschrift hebben we het concept van stress gdntroduceerd en emotionele leren en geheugen, een aspect positief be'invloed door stress en stresshormonen. We hebben verder de effecten die vaak gezien worden na chronische stress geintroduceerd, die kunnen leiden tot verschillende schadelijke aandoeningen, waaronder depressic. We weten allemaal dat niet alleervaringen even goed worden opgeslagen in ons geheugen. Significante en emotionele gebeurlenissen zijn vooral goed Ie onthouden. Vit uitgebreide gegevens blijkt dat de stress hormonen die vrijkomen tijdens en na zulke ervaringen, de neurobiologisch processen die verantwoordelijk zijn voor de verbeterde consolidatie en opslag van emotionele ervaringen in lange-termijn geheugen moduleren. Het eerste deel van dil proefschrift was gericht op het verder ontleden van de neurobiologisch circuits en mechanismen geassocieerd met emotionele geheugenvorming. De experimentele aanpak is gebaseerd op gedragsexperimenten en farmacologische manipulaties gebruikt om de glucocorticdid-geinduceerde modulatie van de consolidatie processen, die betrokken zijn bij de opslag van emotionele ervaringen nader te onderzoeken. In hoofdstuk 2 wordt eerst de be!angrijkste techniek die wordt gebruikt in Dee! I, stereotactische operatiesgdntroduceerd. Door een aantal aanpassingen konden we deze al lang bestaande procedure verfijnen en het welzijn en overleving van de dieren aanzienlijk verhogen. Door gebruik te maken van deze techniek in hoofdstuk 3, hebben we canules in de insulaire cortex (Ie) geYmplanteerd en konden we de betrokkenheid van de insulaire cortex (Ie) bij de effecten van glucocorticolden op de consolidatie van aversieve gebeurtenissen bestuderen. Door het gebruik van het "inhibitory avoidance" paradigma konden wij aantonen dat administratie van de specifieke glucocorticoid receptor (GR) agonist RV 28362 direct (maar niet 3 uur) na de training dosis-afhankelijk de 48-uurs retentie preslaties verbeterde. Met behulp van een gemodificeerde versie van de "inhibitory avoidance" taak, hebben we verder ontdekt dat de Ie de glucocorticolde werking van de versterking van het geheugen van beiden componenten van de taak bemiddelt/verbetert. Op basis van deze bevindingen veronderstellen we dat de Ie vee I breder bij de versterking van emotioneel geheugen betrokken is en waarschijnlijk deel van een groter netwerk voor de detectie van opvallende informatie uitmaakt

Sex differences in stress responses:Focus on ovarian hormones

Women in the reproductive age are more vulnerable to develop affective disorders than men. This difference may attribute to anatomical differences, hormonal influences and environmental factors such as stress. However, the higher prevalence in women normalizes once menopause is established, suggesting that ovarian hormones may play an important role in the development of depression in women. Ovarian hormones such as estrogen can pass the brain-blood barrier and bind to cytoplasmatic estrogen receptor (ER)-alpha and ER-beta in different areas of the limbic system. During stress. estrogen can modulate the behavioral and neurobiological response depending on the concentrations of estrogen. In this review we present evidence for disparate effects of chronic stress on neuroplasticity and brain activity in male and female rats. Furthermore, we will demonstrate that effects of social support on coping with stress can be mimicked by social housing of rats and that this model can be used for identification of underlying neurobiological mechanisms, including behavior, phosphorylation of CREB and ERK1/2, and brain activity changes as measured with fos expression. Using cyclic administration of estrogen in ovariectomized female rats we could specifically address effects of different plasma estrogen levels and antidepressants on stress-induced neuroplasticity and activity changes. In this model we also studied effects of estrogen on recovery after chronic stress. We conclude that the female brain has a different innate strategy to handle stress than the male brain and that female animal models are necessary for studying the underlying mechanisms and options for treatment. (c) 2009 Elsevier Inc. All rights reserved