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  • Control of Amygdala Circuits by 5-HT Neurons via 5-HT and Glutamate Cotransmission.

    14 February 2018

    The serotonin (5-HT) system and the amygdala are key regulators of emotional behavior. Several lines of evidence suggest that 5-HT transmission in the amygdala is implicated in the susceptibility and drug treatment of mood disorders. Therefore, elucidating the physiological mechanisms through which midbrain 5-HT neurons modulate amygdala circuits could be pivotal in understanding emotional regulation in health and disease. To shed light on these mechanisms, we performed patch-clamp recordings from basal amygdala (BA) neurons in brain slices from mice with channelrhodopsin genetically targeted to 5-HT neurons. Optical stimulation of 5-HT terminals at low frequencies (≤1 Hz) evoked a short-latency excitation of BA interneurons (INs) that was depressed at higher frequencies. Pharmacological analysis revealed that this effect was mediated by glutamate and not 5-HT because it was abolished by ionotropic glutamate receptor antagonists. Optical stimulation of 5-HT terminals at higher frequencies (10-20 Hz) evoked both slow excitation and slow inhibition of INs. These effects were mediated by 5-HT because they were blocked by antagonists of 5-HT2A and 5-HT1A receptors, respectively. These fast glutamate- and slow 5-HT-mediated responses often coexisted in the same neuron. Interestingly, fast-spiking and non-fast-spiking INs displayed differential modulation by glutamate and 5-HT. Furthermore, optical stimulation of 5-HT terminals did not evoke glutamate release onto BA principal neurons, but inhibited these cells directly via activation of 5-HT1A receptors and indirectly via enhanced GABA release. Collectively, these findings suggest that 5-HT neurons exert a frequency-dependent, cell-type-specific control over BA circuitry via 5-HT and glutamate co-release to inhibit the BA output.SIGNIFICANCE STATEMENT The modulation of the amygdala by serotonin (5-HT) is important for emotional regulation and is implicated in the pathogenesis and treatment of affective disorders. Therefore, it is essential to determine the physiological mechanisms through which 5-HT neurons in the dorsal raphe nuclei modulate amygdala circuits. Here, we combined optogenetic, electrophysiological, and pharmacological approaches to study the effects of activation of 5-HT axons in the basal nucleus of the amygdala (BA). We found that 5-HT neurons co-release 5-HT and glutamate onto BA neurons in a cell-type-specific and frequency-dependent manner. Therefore, we suggest that theories on the contribution of 5-HT neurons to amygdala function should be revised to incorporate the concept of 5-HT/glutamate cotransmission.

  • Hippocampal NMDA receptors are important for behavioural inhibition but not for encoding associative spatial memories.

    15 February 2018

    The idea that an NMDA receptor (NMDAR)-dependent long-term potentiation-like process in the hippocampus is the neural substrate for associative spatial learning and memory has proved to be extremely popular and influential. However, we recently reported that mice lacking NMDARs in dentate gyrus and CA1 hippocampal subfields (GluN1(ΔDGCA1) mice) acquired the open field, spatial reference memory watermaze task as well as controls, a result that directly challenges this view. Here, we show that GluN1(ΔDGCA1) mice were not impaired during acquisition of a spatial discrimination watermaze task, during which mice had to choose between two visually identical beacons, based on extramaze spatial cues, when all trials started at locations equidistant between the two beacons. They were subsequently impaired on test trials starting from close to the decoy beacon, conducted post-acquisition. GluN1(ΔDGCA1) mice were also impaired during reversal of this spatial discrimination. Thus, contrary to the widely held belief, hippocampal NMDARs are not required for encoding associative, long-term spatial memories. Instead, hippocampal NMDARs, particularly in CA1, act as part of a comparator system to detect and resolve conflicts arising when two competing, behavioural response options are evoked concurrently, through activation of a behavioural inhibition system. These results have important implications for current theories of hippocampal function.

  • Aversive prediction error signals in the amygdala.

    15 February 2018

    Prediction error signals are fundamental to learning. Here, in mice, we show that aversive prediction signals are found in the hemodynamic responses and theta oscillations recorded from the basolateral amygdala. During fear conditioning, amygdala responses evoked by footshock progressively decreased, whereas responses evoked by the auditory cue that predicted footshock concomitantly increased. Unexpected footshock evoked larger amygdala responses than expected footshock. The magnitude of the amygdala response to the footshock predicted behavioral responses the following day. The omission of expected footshock led to a decrease below baseline in the amygdala response suggesting a negative aversive prediction error signal. Thus, in mice, amygdala activity conforms to temporal difference models of aversive learning.

  • LRRK2 BAC transgenic rats develop progressive, L-DOPA-responsive motor impairment, and deficits in dopamine circuit function.

    9 February 2018

    Mutations in leucine-rich repeat kinase 2 (LRRK2) lead to late-onset, autosomal dominant Parkinson's disease, characterized by the degeneration of dopamine neurons of the substantia nigra pars compacta, a deficit in dopamine neurotransmission and the development of motor and non-motor symptoms. The most prevalent Parkinson's disease LRRK2 mutations are located in the kinase (G2019S) and GTPase (R1441C) encoding domains of LRRK2. To better understand the sequence of events that lead to progressive neurophysiological deficits in vulnerable neurons and circuits in Parkinson's disease, we have generated LRRK2 bacterial artificial chromosome transgenic rats expressing either G2019S or R1441C mutant, or wild-type LRRK2, from the complete human LRRK2 genomic locus, including endogenous promoter and regulatory regions. Aged (18-21 months) G2019S and R1441C mutant transgenic rats exhibit L-DOPA-responsive motor dysfunction, impaired striatal dopamine release as determined by fast-scan cyclic voltammetry, and cognitive deficits. In addition, in vivo recordings of identified substantia nigra pars compacta dopamine neurons in R1441C LRRK2 transgenic rats reveal an age-dependent reduction in burst firing, which likely results in further reductions to striatal dopamine release. These alterations to dopamine circuit function occur in the absence of neurodegeneration or abnormal protein accumulation within the substantia nigra pars compacta, suggesting that nigrostriatal dopamine dysfunction precedes detectable protein aggregation and cell death in the development of Parkinson's disease. In conclusion, our longitudinal deep-phenotyping provides novel insights into how the genetic burden arising from human mutant LRRK2 manifests as early pathophysiological changes to dopamine circuit function and highlights a potential model for testing Parkinson's therapeutics.

  • Prodromal Parkinsonism and Neurodegenerative Risk Stratification in REM Sleep Behavior Disorder.

    5 February 2018

    Objectives: Rapid eye movement (REM) sleep behavior disorder (RBD) is the most specific marker of prodromal alpha-synucleinopathies. We sought to delineate the baseline clinical characteristics of RBD and evaluate risk stratification models. Methods: Clinical assessments were performed in 171 RBD, 296 control, and 119 untreated Parkinson's (PD) participants. Putative risk measures were assessed as predictors of prodromal neurodegeneration, and Movement Disorders Society (MDS) criteria for prodromal PD were applied. Participants were screened for common leucine-rich repeat kinase 2 (LRRK2)/glucocerebrosidase gene (GBA) gene mutations. Results: Compared to controls, participants with RBD had higher rates of solvent exposure, head injury, smoking, obesity, and antidepressant use. GBA mutations were more common in RBD, but no LRRK2 mutations were found. RBD participants performed significantly worse than controls on Unified Parkinson's Disease Rating Scale (UPDRS)-III, timed "get-up-and-go", Flamingo test, Sniffin Sticks, and cognitive tests and had worse measures of constipation, quality of life (QOL), and orthostatic hypotension. For all these measures except UPDRS-III, RBD and PD participants were equally impaired. Depression, anxiety, and apathy were worse in RBD compared to PD participants. Stratification of people with RBD according to antidepressant use, obesity, and age altered the odds ratio (OR) of hyposmia compared to controls from 3.4 to 45.5. 74% (95% confidence interval [CI] 66%, 80%) of RBD participants met the MDS criteria for probable prodromal Parkinson's compared to 0.3% (95% CI 0.009%, 2%) of controls. Conclusions: RBD are impaired across a range of clinical measures consistent with prodromal PD and suggestive of a more severe nonmotor subtype. Clinical risk stratification has the potential to select higher risk patients for neuroprotective interventions.

  • The anatomy of apathy: A neurocognitive framework for amotivated behaviour.

    5 February 2018

    Apathy is a debilitating syndrome associated with many neurological disorders, including several common neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease, and focal lesion syndromes such as stroke. Here, we review neuroimaging studies to identify anatomical correlates of apathy, across brain disorders. Our analysis reveals that apathy is strongly associated with disruption particularly of dorsal anterior cingulate cortex (dACC), ventral striatum (VS) and connected brain regions. Remarkably, these changes are consistent across clinical disorders and imaging modalities. Review of the neuroimaging findings allows us to develop a neurocognitive framework to consider potential mechanisms underlying apathy. According to this perspective, an interconnected group of brain regions - with dACC and VS at its core - plays a crucial role in normal motivated behaviour. Specifically we argue that motivated behaviour requires a willingness to work, to keep working, and to learn what is worth working for. We propose that deficits in any one or more of these processes can lead to the clinical syndrome of apathy, and outline specific approaches to test this hypothesis. A richer neurobiological understanding of the mechanisms underlying apathy should ultimately facilitate development of effective therapies for this disabling condition.