Control of feeding by a bottom-up midbrain-subthalamic pathway.

Investigative exploration and foraging leading to food consumption have vital importance, but are not well-understood. Since GABAergic inputs to the lateral and ventrolateral periaqueductal gray (l/vlPAG) control such behaviors, we dissected the role of vgat-expressing GABAergic l/vlPAG cells in exploration, foraging and hunting. Here, we show that in mice vgat l/vlPAG cells encode approach to food and consumption of both live prey and non-prey foods. The activity of these cells is necessary and sufficient for inducing food-seeking leading to subsequent consumption. Activation of vgat l/vlPAG cells produces exploratory foraging and compulsive eating without altering defensive behaviors. Moreover, l/vlPAG vgat cells are bidirectionally interconnected to several feeding, exploration and investigation nodes, including the zona incerta. Remarkably, the vgat l/vlPAG projection to the zona incerta bidirectionally controls approach towards food leading to consumption. These data indicate the PAG is not only a final downstream target of top-down exploration and foraging-related inputs, but that it also influences these behaviors through a bottom-up pathway.

Synaptic and intrinsic plasticity within overlapping lateral amygdala ensembles following fear conditioning.

Introduction: New learning results in modulation of intrinsic plasticity in the underlying brain regions. Such changes in intrinsic plasticity can influence allocation and encoding of future memories such that new memories encoded during the period of enhanced excitability are linked to the original memory. The temporal window during which the two memories interact depends upon the time course of intrinsic plasticity following new learning. Methods: Using the well-characterized lateral amygdala-dependent auditory fear conditioning as a behavioral paradigm, we investigated the time course of changes in intrinsic excitability within lateral amygdala neurons. Results: We found transient changes in the intrinsic excitability of amygdala neurons. Neuronal excitability was increased immediately following fear conditioning and persisted for up to 4 days post-learning but was back to naïve levels 10 days following fear conditioning. We also determined the relationship between learning-induced intrinsic and synaptic plasticity. Synaptic plasticity following fear conditioning was evident for up to 24 h but not 4 days later. Importantly, we demonstrated that the enhanced neuronal intrinsic excitability was evident in many of the same neurons that had undergone synaptic plasticity immediately following fear conditioning. Interestingly, such a correlation between synaptic and intrinsic plasticity following fear conditioning was no longer present 24 h post-learning. Discussion: These data demonstrate that intrinsic and synaptic changes following fear conditioning are transient and co-localized to the same neurons. Since intrinsic plasticity following fear conditioning is an important determinant for the allocation and consolidation of future amygdala-dependent memories, these findings establish a time course during which fear memories may influence each other.

A dual-pathway architecture enables chronic stress to promote habit formation.

Chronic stress can change how we learn and, thus, how we make decisions by promoting the formation of inflexible, potentially maladaptive, habits. Here we investigated the neuronal circuit mechanisms that enable this. Using a multifaceted approach in male and female mice, we reveal a dual pathway, amygdala-striatal, neuronal circuit architecture by which a recent history of chronic stress shapes learning to disrupt flexible goal-directed behavior in favor of inflexible habits. Chronic stress inhibits activity of basolateral amygdala projections to the dorsomedial striatum to impede the action-outcome learning that supports flexible, goal-directed decisions. Stress also increases activity in direct central amygdala projections to the dorsomedial striatum to promote the formation of rigid, inflexible habits. Thus, stress exerts opposing effects on two amygdala-striatal pathways to promote premature habit formation. These data provide neuronal circuit insights into how chronic stress shapes learning and decision making, and help understand how stress can lead to the disrupted decision making and pathological habits that characterize substance use disorders and other psychiatric conditions.

Miniscope-LFOV: A large-field-of-view, single-cell-resolution, miniature microscope for wired and wire-free imaging of neural dynamics in freely behaving animals.

Imaging large-population, single-cell fluorescent dynamics in freely behaving animals larger than mice remains a key endeavor of neuroscience. We present a large-field-of-view open-source miniature microscope (MiniLFOV) designed for large-scale (3.6 mm × 2.7 mm), cellular resolution neural imaging in freely behaving rats. It has an electrically adjustable working distance of up to 3.5 mm ± 100 µm, incorporates an absolute head orientation sensor, and weighs only 13.9 g. The MiniLFOV is capable of both deep brain and cortical imaging and has been validated in freely behaving rats by simultaneously imaging >1000 GCaMP7s-expressing neurons in the hippocampal CA1 layer and in head-fixed mice by simultaneously imaging ~2000 neurons in the dorsal cortex through a cranial window. The MiniLFOV also supports optional wire-free operation using a novel, wire-free data acquisition expansion board. We expect that this new open-source implementation of the UCLA Miniscope platform will enable researchers to address novel hypotheses concerning brain function in freely behaving animals.

Local memory allocation recruits memory ensembles across brain regions.

Memories are thought to be stored in ensembles of neurons across multiple brain regions. However, whether and how these ensembles are coordinated at the time of learning remains largely unknown. Here, we combined CREB-mediated memory allocation with transsynaptic retrograde tracing to demonstrate that the allocation of aversive memories to a group of neurons in one brain region directly affects the allocation of interconnected neurons in upstream brain regions in a behavioral- and brain region-specific manner in mice. Our analysis suggests that this cross-regional recruitment of presynaptic neurons is initiated by downstream memory neurons through a retrograde mechanism. Together with statistical modeling, our results indicate that in addition to the anterograde flow of information between brain regions, the establishment of interconnected, brain-wide memory traces relies on a retrograde mechanism that coordinates memory ensembles at the time of learning.

Dorsal premammillary projection to periaqueductal gray controls escape vigor from innate and conditioned threats.

Escape from threats has paramount importance for survival. However, it is unknown if a single circuit controls escape vigor from innate and conditioned threats. Cholecystokinin (cck)-expressing cells in the hypothalamic dorsal premammillary nucleus (PMd) are necessary for initiating escape from innate threats via a projection to the dorsolateral periaqueductal gray (dlPAG). We now show that in mice PMd-cck cells are activated during escape, but not other defensive behaviors. PMd-cck ensemble activity can also predict future escape. Furthermore, PMd inhibition decreases escape speed from both innate and conditioned threats. Inhibition of the PMd-cck projection to the dlPAG also decreased escape speed. Intriguingly, PMd-cck and dlPAG activity in mice showed higher mutual information during exposure to innate and conditioned threats. In parallel, human functional magnetic resonance imaging data show that a posterior hypothalamic-to-dlPAG pathway increased activity during exposure to aversive images, indicating that a similar pathway may possibly have a related role in humans. Our data identify the PMd-dlPAG circuit as a central node, controlling escape vigor elicited by both innate and conditioned threats.

Modulation of intrinsic excitability as a function of learning within the fear conditioning circuit.

Experience-dependent neuronal plasticity is a fundamental substrate of learning and memory. Intrinsic excitability is a form of neuronal plasticity that can be altered by learning and indicates the pattern of neuronal responding to external stimuli (e.g. a learning or synaptic event). Associative fear conditioning is one form of learning that alters intrinsic excitability, reflecting an experience-dependent change in neuronal function. After fear conditioning, intrinsic excitability changes are evident in brain regions that are a critical part of the fear circuit, including the amygdala, hippocampus, retrosplenial cortex, and prefrontal cortex. Some of these changes are transient and/or reversed by extinction as well as learning-specific (i.e. they are not observed in neurons from control animals). This review will explore how intrinsic neuronal excitability changes within brain structures that are critical for fear learning, and it will also discuss evidence promoting intrinsic excitability as a vital mechanism of associative fear memories. This work has raised interesting questions regarding the role of fear learning in changes of intrinsic excitability within specific subpopulations of neurons, including those that express immediate early genes and thus demonstrate experience-dependent activity, as well as in neurons classified as having a specific firing type (e.g. burst-spiking vs. regular-spiking). These findings have interesting implications for how intrinsic excitability can serve as a neural substrate of learning and memory, and suggest that intrinsic plasticity within specific subpopulations of neurons may promote consolidation of the memory trace in a flexible and efficient manner.

Effect of different stripping techniques on pulpal temperature: in vitro study.

INTRODUCTION: Proximal stripping of enamel is a routine clinical procedure employed in orthodontics to create space or for balancing tooth size discrepancies. This procedure may result in heat transfer to the pulp, predisposing it to histopathological changes and necrosis of the pulp tissue. OBJECTIVE: To measure the temperature changes in the pulp chamber during different stripping procedures. METHODS: 80 proximal surfaces of 40 extracted human premolar teeth were stripped using four techniques: diamond burs in air-rotor handpiece with air-water spray; diamond burs in micromotor handpiece, with and without a coolant spray; and hand-held diamond strips. A J-type thermocouple connected to a digital thermometer was inserted into the pulp chamber for evaluation of temperature during the stripping procedure. RESULTS: An increase in the pulpal temperature was observed for all stripping method. Diamond burs in micromotor handpiece without coolant resulted in the higher increase in temperature (3.5oC), followed by hand-held diamond strips (2.8oC), diamond burs in air-rotor with air-water spray (1.9oC); and the smallest increase was seen with diamond burs in micromotor handpiece with coolant (1.65oC). None of the techniques resulted in temperature increase above the critical level of 5.5oC. CONCLUSION: Frictional heat produced with different stripping techniques results in increase in the pulpal temperature, therefore, caution is advised during this procedure. A coolant spray can limit the increase in temperature of the pulp.

Effect of different stripping techniques on pulpal temperature: in vitro study

ABSTRACT Introduction: Proximal stripping of enamel is a routine clinical procedure employed in orthodontics to create space or for balancing tooth size discrepancies. This procedure may result in heat transfer to the pulp, predisposing it to histopathological changes and necrosis of the pulp tissue. Objective: To measure the temperature changes in the pulp chamber during different stripping procedures. Methods: 80 proximal surfaces of 40 extracted human premolar teeth were stripped using four techniques: diamond burs in air-rotor handpiece with air-water spray; diamond burs in micromotor handpiece, with and without a coolant spray; and hand-held diamond strips. A J-type thermocouple connected to a digital thermometer was inserted into the pulp chamber for evaluation of temperature during the stripping procedure. Results: An increase in the pulpal temperature was observed for all stripping method. Diamond burs in micromotor handpiece without coolant resulted in the higher increase in temperature (3.5oC), followed by hand-held diamond strips (2.8oC), diamond burs in air-rotor with air-water spray (1.9oC); and the smallest increase was seen with diamond burs in micromotor handpiece with coolant (1.65oC). None of the techniques resulted in temperature increase above the critical level of 5.5oC. Conclusion: Frictional heat produced with different stripping techniques results in increase in the pulpal temperature, therefore, caution is advised during this procedure. A coolant spray can limit the increase in temperature of the pulp.

RESUMO Introdução: o desgaste proximal do esmalte é um procedimento clínico rotineiro utilizado na Ortodontia para se criar espaços ou equilibrar discrepâncias de tamanho dentário. Esse procedimento pode resultar em transferência de calor para a polpa, predispondo-a a mudanças histopatológicas e necrose do tecido pulpar. Objetivo: medir as mudanças de temperatura na câmara pulpar durante diferentes procedimentos de desgaste interproximal. Métodos: 80 superfícies proximais de 40 pré-molares humanos foram desgastadas utilizando-se quatro técnicas diferentes: brocas diamantadas em motor a ar (alta rotação) com spray de água e ar; brocas diamantadas em micromotor (baixa rotação) com e sem spray de resfriamento; e tiras diamantadas manuais. Um par termoelétrico do tipo J conectado a um termômetro digital foi inserido na câmara pulpar para avaliação da temperatura durante o desgaste proximal. Resultados: foi observado um aumento da temperatura da câmara pulpar em todos os métodos de desgaste proximal. As brocas diamantadas em micromotor sem resfriamento foram responsáveis pelo maior aumento da temperatura (3,5oC), seguidas pelas lixas diamantadas manuais (2,8oC) e brocas diamantadas em motor a ar (alta rotação) com spray de água e ar (1,9oC). O menor aumento foi observado com as brocas diamantadas em micromotor (baixa rotação) com resfriamento (1,65oC). Nenhuma das técnicas elevou a temperatura acima do nível crítico de 5,5oC. Conclusão: o aquecimento friccional produzido pelas diferentes técnicas de desgaste proximal levou ao aumento da temperatura da câmara pulpar; assim, cuidados devem ser tomados durante esse procedimento. O spray de água e ar pode limitar o aumento da temperatura da polpa.

Memory formation depends on both synapse-specific modifications of synaptic strength and cell-specific increases in excitability.

The modification of synaptic strength produced by long-term potentiation (LTP) is widely thought to underlie memory storage. Indeed, given that hippocampal pyramidal neurons have >10,000 independently modifiable synapses, the potential for information storage by synaptic modification is enormous. However, recent work suggests that CREB-mediated global changes in neuronal excitability also play a critical role in memory formation. Because these global changes have a modest capacity for information storage compared with that of synaptic plasticity, their importance for memory function has been unclear. Here we review the newly emerging evidence for CREB-dependent control of excitability and discuss two possible mechanisms. First, the CREB-dependent transient change in neuronal excitability performs a memory-allocation function ensuring that memory is stored in ways that facilitate effective linking of events with temporal proximity (hours). Second, these changes may promote cell-assembly formation during the memory-consolidation phase. It has been unclear whether such global excitability changes and local synaptic mechanisms are complementary. Here we argue that the two mechanisms can work together to promote useful memory function.

CCR5 is a suppressor for cortical plasticity and hippocampal learning and memory.

Although the role of CCR5 in immunity and in HIV infection has been studied widely, its role in neuronal plasticity, learning and memory is not understood. Here, we report that decreasing the function of CCR5 increases MAPK/CREB signaling, long-term potentiation (LTP), and hippocampus-dependent memory in mice, while neuronal CCR5 overexpression caused memory deficits. Decreasing CCR5 function in mouse barrel cortex also resulted in enhanced spike timing dependent plasticity and consequently, dramatically accelerated experience-dependent plasticity. These results suggest that CCR5 is a powerful suppressor for plasticity and memory, and CCR5 over-activation by viral proteins may contribute to HIV-associated cognitive deficits. Consistent with this hypothesis, the HIV V3 peptide caused LTP, signaling and memory deficits that were prevented by Ccr5 knockout or knockdown. Overall, our results demonstrate that CCR5 plays an important role in neuroplasticity, learning and memory, and indicate that CCR5 has a role in the cognitive deficits caused by HIV.

Learning enhances intrinsic excitability in a subset of lateral amygdala neurons.

Learning-induced modulation of neuronal intrinsic excitability is a metaplasticity mechanism that can impact the acquisition of new memories. Although the amygdala is important for emotional learning and other behaviors, including fear and anxiety, whether learning alters intrinsic excitability within the amygdala has received very little attention. Fear conditioning was combined with intracellular recordings to investigate the effects of learning on the intrinsic excitability of lateral amygdala (LA) neurons. To assess time-dependent changes, brain slices were prepared either immediately or 24-h post-conditioning. Fear conditioning significantly enhanced excitability of LA neurons, as evidenced by both decreased afterhyperpolarization (AHP) and increased neuronal firing. These changes were time-dependent such that reduced AHPs were evident at both time points whereas increased neuronal firing was only observed at the later (24-h) time point. Moreover, these changes occurred within a subset (32%) of LA neurons. Previous work also demonstrated that learning-related changes in synaptic plasticity are also evident in less than one-third of amygdala neurons, suggesting that the neurons undergoing intrinsic plasticity may be critical for fear memory. These data may be clinically relevant as enhanced LA excitability following fear learning could influence future amygdala-dependent behaviors.

Learning to learn - intrinsic plasticity as a metaplasticity mechanism for memory formation.

"Use it or lose it" is a popular adage often associated with use-dependent enhancement of cognitive abilities. Much research has focused on understanding exactly how the brain changes as a function of experience. Such experience-dependent plasticity involves both structural and functional alterations that contribute to adaptive behaviors, such as learning and memory, as well as maladaptive behaviors, including anxiety disorders, phobias, and posttraumatic stress disorder. With the advancing age of our population, understanding how use-dependent plasticity changes across the lifespan may also help to promote healthy brain aging. A common misconception is that such experience-dependent plasticity (e.g., associative learning) is synonymous with synaptic plasticity. Other forms of plasticity also play a critical role in shaping adaptive changes within the nervous system, including intrinsic plasticity - a change in the intrinsic excitability of a neuron. Intrinsic plasticity can result from a change in the number, distribution or activity of various ion channels located throughout the neuron. Here, we review evidence that intrinsic plasticity is an important and evolutionarily conserved neural correlate of learning. Intrinsic plasticity acts as a metaplasticity mechanism by lowering the threshold for synaptic changes. Thus, learning-related intrinsic changes can facilitate future synaptic plasticity and learning. Such intrinsic changes can impact the allocation of a memory trace within a brain structure, and when compromised, can contribute to cognitive decline during the aging process. This unique role of intrinsic excitability can provide insight into how memories are formed and, more interestingly, how neurons that participate in a memory trace are selected. Most importantly, modulation of intrinsic excitability can allow for regulation of learning ability - this can prevent or provide treatment for cognitive decline not only in patients with clinical disorders but also in the aging population.

Trace fear conditioning enhances synaptic and intrinsic plasticity in rat hippocampus.

Experience-dependent synaptic and intrinsic plasticity are thought to be important substrates for learning-related changes in behavior. The present study combined trace fear conditioning with both extracellular and intracellular hippocampal recordings to study learning-related synaptic and intrinsic plasticity. Rats received one session of trace fear conditioning, followed by a brief conditioned stimulus (CS) test the next day. To relate behavioral performance with measures of hippocampal CA1 physiology, brain slices were prepared within 1 h of the CS test. In trace-conditioned rats, both synaptic plasticity and intrinsic excitability were significantly correlated with behavior such that better learning corresponded with enhanced long-term potentiation (LTP; r = 0.64, P < 0.05) and a smaller postburst afterhyperpolarization (AHP; r = -0.62, P < 0.05). Such correlations were not observed in pseudoconditioned rats, whose physiological data were comparable to those of poor learners and naive and chamber-exposed control rats. In addition, acquisition of trace fear conditioning did not enhance basal synaptic responses. Thus these data suggest that within the hippocampus both synaptic and intrinsic mechanisms are involved in the acquisition of trace fear conditioning.