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Dynamic regulation of the cytoskeletal factor ABLIM3 controls the precision of memory representations in rodent models of post-traumatic stress disorder and age-related cognitive impairment. Memories become less precise and generalized over time as memory traces reorganize in hippocampal–cortical networks. Increased time-dependent loss of memory precision is characterized by an overgeneralization of fear in individuals with post-traumatic stress disorder (PTSD) or age-related cognitive impairments. In the hippocampal dentate gyrus (DG), memories are thought to be encoded by so-called 'engram-bearing' dentate granule cells (eDGCs). Here we show, using rodents, that contextual fear conditioning increases connectivity between eDGCs and inhibitory interneurons (INs) in the downstream hippocampal CA3 region. We identify actin-binding LIM protein 3 (ABLIM3) as a mossy-fiber-terminal-localized cytoskeletal factor whose levels decrease after learning. Downregulation of ABLIM3 expression in DGCs was sufficient to increase connectivity with CA3 stratum lucidum INs (SLINs), promote parvalbumin (PV)-expressing SLIN activation, enhance feedforward inhibition onto CA3 and maintain a fear memory engram in the DG over time. Furthermore, downregulation of ABLIM3 expression in DGCs conferred conditioned context-specific reactivation of memory traces in hippocampal–cortical and amygdalar networks and decreased fear memory generalization at remote (i.e., distal) time points. Consistent with the observation of age-related hyperactivity of CA3, learning failed to increase DGC–SLIN connectivity in 17-month-old mice, whereas downregulation of ABLIM3 expression was sufficient to restore DGC–SLIN connectivity, increase PV+ SLIN activation and improve the precision of remote memories. These studies exemplify a connectivity-based strategy that targets a molecular brake of feedforward inhibition in DG–CA3 and may be harnessed to decrease time-dependent memory generalization in individuals with PTSD and improve memory precision in aging individuals.

Drug-associated stimuli (cues) can usurp potent control of behavior in individuals with substance use disorders; and these effects are often attributed to altered dopamine transmission. However, there is much debate over the way in which dopamine signaling changes over the course of chronic drug use. Here, we carried out longitudinal recording and manipulation of cue-evoked dopamine release in the core of the nucleus accumbens across phases of substance use in male rats. We show that, in a subset of individuals that exhibit increased cue reactivity and escalated drug consumption, this signaling undergoes diametrically opposed changes in amplitude, determined by the context in which the cue was presented. Dopamine evoked by non-contingent cue presentation (independent of the animal’s actions) increases over drug use, producing greater cue reactivity; whereas dopamine evoked by contingent cue presentation (dependent on the animal’s actions) decreases over drug use, producing escalation of drug consumption. Therefore, despite being in opposite directions, these dopamine trajectories each promote cardinal features of substance use disorders. Here authors demonstrate how opposing trajectories of dopamine transmission underlie changes in drug seeking and taking over chronic drug use. Increased dopamine to drug cues elevates craving, whereas decreased dopamine produces escalation of drug consumption.

The axonal guidance cue netrin-1 serves a critical role in neural circuit development by promoting growth cone motility, axonal branching, and synaptogenesis. Within the adult mouse brain, expression of the gene encoding ( Ntn1 ) is highly enriched in the ventral midbrain where it is expressed in both GABAergic and dopaminergic neurons, but its function in these cell types in the adult system remains largely unknown. To address this, we performed viral-mediated, cell-type specific CRISPR-Cas9 mutagenesis of Ntn1 in the ventral tegmental area (VTA) of adult mice. Ntn1 loss-of-function in either cell type resulted in a significant reduction in excitatory postsynaptic connectivity. In dopamine neurons, the reduced excitatory tone had a minimal phenotypic behavioral outcome; however, reduced glutamatergic tone on VTA GABA neurons induced behaviors associated with a hyperdopaminergic phenotype. Simultaneous loss of Ntn1 function in both cell types largely rescued the phenotype observed in the GABA-only mutagenesis. These findings demonstrate an important role for Ntn1 in maintaining excitatory connectivity in the adult midbrain and that a balance in this connectivity within two of the major cell types of the VTA is critical for the proper functioning of the mesolimbic system.

Neuropeptides play an important role in modulating mesolimbic system function. However, while synaptic inputs to the ventral tegmental area (VTA) have been extensively mapped, the sources of many neuropeptides are not well resolved. Here, we mapped the anatomical locations of three neuropeptide inputs to the VTA: neurotensin (NTS), corticotrophin releasing factor (CRF), and neurokinin B (NkB). Among numerous labeled inputs we identified the bed nucleus of the stria terminalis (BNST) as a major source of all three peptides, containing similar numbers of NTS, CRF, and NkB VTA projection neurons. Approximately 50% of BNST to VTA inputs co-expressed two or more of the peptides examined. Consistent with this expression pattern, analysis of calcium dynamics in the terminals of these inputs in the VTA revealed both common and distinct patterns of activation during appetitive and aversive conditioning. These data demonstrate additional diversification of the mesolimbic dopamine system through partially overlapping neuropeptidergic inputs.

Fast-acting neurotransmitters and slow, modulatory neuropeptides are co-released from neurons in the central nervous system, albeit from distinct synaptic vesicles 1 . The mechanisms of how co-released neurotransmitters and neuropeptides that have opposing actions—for example, stimulatory versus inhibitory—work together to exert control of neural circuit output remain unclear. This has been difficult to resolve owing to the inability to selectively isolate these signalling pathways in a cell- and circuit-specific manner. Here we developed a genetic-based anatomical disconnect procedure that utilizes distinct DNA recombinases to independently facilitate CRISPR–Cas9 mutagenesis 2 of neurotransmitter- and neuropeptide-related genes in distinct cell types in two different brain regions simultaneously. We demonstrate that neurons within the lateral hypothalamus that produce the stimulatory neuropeptide neurotensin and the inhibitory neurotransmitter GABA (γ-aminobutyric acid) utilize these signals to coordinately activate dopamine-producing neurons of the ventral tegmental area. We show that GABA release from lateral hypothalamus neurotensin neurons inhibits GABA neurons within the ventral tegmental area, disinhibiting dopamine neurons and causing a rapid rise in calcium, whereas neurotensin directly generates a slow inactivating calcium signal in dopamine neurons that is dependent on the expression of neurotensin receptor 1 (Ntsr1). We further show that these two signals work together to regulate dopamine neuron responses to maximize behavioural responding. Thus, a neurotransmitter and a neuropeptide with opposing signals can act on distinct timescales through different cell types to enhance circuit output and optimize behaviour. CRISPR–Cas9 mutagenesis studies in mice demonstrate co-release of a neurotransmitter and a neuropeptide with opposing signals that stimulate the ventral tegmental area dopamine system through coordinated actions on different cells at different time scales.

A neural circuit from the parabrachial nucleus to the central nucleus of the amygdala mediates appetite suppression. Neural circuitry closely linked to appetite modulation The parabrachial nucleus (PBN) is an area of the brainstem containing subpopulations of neurons associated with taste, sodium intake, respiration, pain, thermosensation and appetite suppression. Partly because of the heterogeneous mix of cells making up this structure, it has proved difficult to identify the specific pathways driving appetite suppression. Now, using a variety of tools including optogenetic and pharmacogenetic analysis, Richard Palmiter and colleagues identify active calcitonin gene-related peptide-expressing neurons, projecting from the PBN to the central nucleus of the amygdala as a critical circuit driving appetite suppression. By contrast, inhibition of these neurons leads to increased feeding, suggesting that this neural circuit may provide targets for therapeutic intervention to both suppress and promote appetite. Appetite suppression occurs after a meal and in conditions when it is unfavourable to eat, such as during illness or exposure to toxins. A brain region proposed to play a role in appetite suppression is the parabrachial nucleus 1 , 2 , 3 , a heterogeneous population of neurons surrounding the superior cerebellar peduncle in the brainstem. The parabrachial nucleus is thought to mediate the suppression of appetite induced by the anorectic hormones amylin and cholecystokinin 2 , as well as by lithium chloride and lipopolysaccharide, compounds that mimic the effects of toxic foods and bacterial infections, respectively 4 , 5 , 6 . Hyperactivity of the parabrachial nucleus is also thought to cause starvation after ablation of orexigenic agouti-related peptide neurons in adult mice 1 , 7 . However, the identities of neurons in the parabrachial nucleus that regulate feeding are unknown, as are the functionally relevant downstream projections. Here we identify calcitonin gene-related peptide-expressing neurons in the outer external lateral subdivision of the parabrachial nucleus that project to the laterocapsular division of the central nucleus of the amygdala as forming a functionally important circuit for suppressing appetite. Using genetically encoded anatomical, optogenetic 8 and pharmacogenetic 9 tools, we demonstrate that activation of these neurons projecting to the central nucleus of the amygdala suppresses appetite. In contrast, inhibition of these neurons increases food intake in circumstances when mice do not normally eat and prevents starvation in adult mice whose agouti-related peptide neurons are ablated. Taken together, our data demonstrate that this neural circuit from the parabrachial nucleus to the central nucleus of the amygdala mediates appetite suppression in conditions when it is unfavourable to eat. This neural circuit may provide targets for therapeutic intervention to overcome or promote appetite.

Starving animals are less likely to defend their home territory and more likely to engage in risky foraging behaviors. This work describes a circuit involving hypothalamic AgRP neurons projecting to neurons in the medial nucleus of the amygdala and their projections to the bed nucleus of the stria terminalis, which, when activated, mimics these behaviors in mice that are well fed. In the face of starvation, animals will engage in high-risk behaviors that would normally be considered maladaptive. Starving rodents, for example, will forage in areas that are more susceptible to predators and will also modulate aggressive behavior within a territory of limited or depleted nutrients. The neural basis of these adaptive behaviors likely involves circuits that link innate feeding, aggression and fear. Hypothalamic agouti-related peptide (AgRP)-expressing neurons are critically important for driving feeding and project axons to brain regions implicated in aggression and fear. Using circuit-mapping techniques in mice, we define a disynaptic network originating from a subset of AgRP neurons that project to the medial nucleus of the amygdala and then to the principal bed nucleus of the stria terminalis, which suppresses territorial aggression and reduces contextual fear. We propose that AgRP neurons serve as a master switch capable of coordinating behavioral decisions relative to internal state and environmental cues.

The ventral tegmental area (VTA) is important for reward processing and motivation. The anatomic organization of neurotransmitter-specific inputs to the VTA remains poorly resolved. In the present study, we mapped the major neurotransmitter projections to the VTA through cell-type-specific retrograde and anterograde tracing. We found that glutamatergic inputs arose from a variety of sources and displayed some connectivity biases toward specific VTA cell types. The sources of GABAergic projections were more widespread, displayed a high degree of differential innervation of subregions in the VTA and were largely biased toward synaptic contact with local GABA neurons. Inactivation of GABA release from the two major sources, locally derived versus distally derived, revealed distinct roles for these projections in behavioral regulation. Optogenetic manipulation of individual distal GABAergic inputs also revealed differential behavioral effects. These results demonstrate that GABAergic projections to the VTA are a major contributor to the regulation and diversification of the structure.Soden et al. use cell-type-specific retrograde tracing to identify neurotransmitter-specific inputs to the ventral tegmental area, uncovering an underappreciated number of GABAergic inputs with diverse innervation patterns and behavioral functions.

The lateral amygdala (LA) acquires differential coding of predictive and non-predictive fear stimuli that is critical for proper fear memory assignment. The neurotransmitter dopamine is an important modulator of LA activity and facilitates fear memory formation, but whether dopamine neurons aid in the establishment of discriminative fear coding by the LA is unknown. NMDA-type glutamate receptors in dopamine neurons are critical for the prevention of generalized fear following an aversive experience, suggesting a potential link between a cell autonomous function of NMDAR in dopamine neurons and fear coding by the LA. Here, we utilized mice with a selective genetic inactivation functional NMDARs in dopamine neurons (DAT-NR1 KO mice) combined with behavior, in vivo electrophysiology, and ex vivo electrophysiology in LA neurons to demonstrate that plasticity underlying differential fear coding in the LA is regulated by NMDAR signaling in dopamine neurons and alterations in this plasticity is associated non-discriminative cued-fear responses. When we experience a situation that causes us to feel fearful, the brain processes information about the events that led up to it. This information is encoded by groups of nerve cells called neurons in a region of the brain called the lateral amygdala. The nerve cells communicate with each other through chemicals called neurotransmitters. At a junction between two neurons—called a synapse—neurotransmitters are released from one cell and influence the activity of the other cell. Long-term changes in the strength of these communications in response to specific cues underlie the formation of memories about fearful events. When these changes occur incorrectly they can lead to memories about particular events becoming inaccurate, which can lead to fear being associated with related, but non-threatening, situations. This ‘generalization’ of fear can lead to generalized anxiety disorder and post-traumatic stress disorder. Dopamine is a neurotransmitter that plays an important role in forming memories of fearful events. However, it is not clear whether neurons that release dopamine are also involved in correctly discriminating fearful events from non-fearful ones. ‘Receptor’ proteins called NMDARs on the surface of neurons that release dopamine are critical for preventing generalized fear. These receptors detect another neurotransmitter called glutamate. Jones et al. used genetics and ‘electrophysiology’ techniques to study these receptors in mice. The experiments show that a gene that encodes part of an NMDAR in dopamine neurons plays a key role in how fear memories are formed. When this gene is selectively switched off in the dopamine neurons, mice are more likely to develop generalized fear and anxiety behaviors after a threatening experience. The experiments also demonstrate that these generalized threat responses are associated with differences in the way the synaptic connections in the lateral amygdala are strengthened. The next major challenge will be to find out which specific synaptic connections are strengthened and to establish how dopamine neuron activity patterns influences this connectivity.

In some individuals, drug-associated cues subsume potent control of behavior, such as the elicitation of drug craving and automatized drug use . The intensity of this cue reactivity is highly predictive of relapse and other clinical outcomes in substance use disorders . It has been postulated that this cue reactivity is driven by augmentation of dopamine release over the course of chronic drug use . Here we carried out longitudinal recording and manipulation of cue-evoked dopamine signaling across phases of substance-use related behavior in rats. We observed a subset of individuals that exhibited increased cue reactivity and escalated drug consumption, two cardinal features of substance use disorders. In these individuals, cue-evoked phasic dopamine release underwent diametrically opposed changes in amplitude, determined by the context in which the cue is presented. Dopamine evoked by non-contingent cue presentation increased over drug use, producing greater cue reactivity; whereas dopamine evoked by contingent cue presentation decreased over drug use, producing escalation of drug consumption. Therefore, despite being in opposite directions, these dopamine trajectories each promote core symptoms of substance use disorders.