The striatum integrates information from multiple brain regions to shape motor learning. The two major projection cell types in striatum target different downstream basal ganglia targets and have ...opposing effects on motivated behavior, yet differential innervation of these neuronal subtypes is not well understood. To examine whether input specificity provides a substrate for information segregation in these circuits, we used a monosynaptic rabies virus system to generate brain-wide maps of neurons that form synapses with direct- or indirect-pathway striatal projection neurons. We discovered that sensory cortical and limbic structures preferentially innervated the direct pathway, whereas motor cortex preferentially targeted the indirect pathway. Thalamostriatal input, dopaminergic input, as well as input from specific cortical layers, was similar onto both pathways. We also confirm synaptic innervation of striatal projection neurons by the raphe and pedunculopontine nuclei. Together, these findings provide a framework for guiding future studies of basal ganglia circuit function.
•Sensory cortical and limbic structures preferentially target direct-pathway neurons•Motor cortex preferentially innervates indirect-pathway neurons•Inputs from thalamus, substantia nigra, and specific cortical layers was similar•Only a small proportion of dopaminergic input was transsynaptically labeled
Striatal direct- and indirect-pathway projection neurons serve distinct motor functions, but the specificity of their synaptic inputs is not known. Wall et al. use genetically targeted rabies virus to generate brain-wide input maps to these pathways.
Ventral tegmental area (VTA) dopamine (DA) neurons have been implicated in reward, aversion, salience, cognition, and several neuropsychiatric disorders. Optogenetic approaches involving transgenic ...Cre-driver mouse lines provide powerful tools for dissecting DA-specific functions. However, the emerging complexity of VTA circuits requires Cre-driver mouse lines that restrict transgene expression to a precisely defined cell population. Because of recent work reporting that VTA DA neurons projecting to the lateral habenula release GABA, but not DA, we performed an extensive anatomical, molecular, and functional characterization of prominent DA transgenic mouse driver lines. We find that transgenes under control of the tyrosine hydroxylase, but not the dopamine transporter, promoter exhibit dramatic non-DA cell-specific expression patterns within and around VTA nuclei. Our results demonstrate how Cre expression in unintentionally targeted cells in transgenic mouse lines can confound the interpretation of supposedly cell-type-specific experiments. This Matters Arising paper is in response to Stamatakis et al. (2013), published in Neuron. See also the Matters Arising Response paper by Stuber et al. (2015), published concurrently with this Matters Arising in Neuron.
Clinical frailty is an important syndrome for clinical care and research, independently predicting mortality and rates of institutionalisation in a range of medical conditions. However, there has ...been little research into the role of frailty in stroke.
This study investigates the effect of frailty on 28-day mortality following ischaemic stroke and outcomes following stroke thrombolysis.
Frailty was measured using the Clinical Frailty Scale (CFS) for all ischaemic stroke admissions aged ≥75 years. Stroke severity was measured using the National Institutes of Health Stroke Scale (NIHSS). 28-day mortality and clinical outcomes were collected retrospectively. Analysis included both dichotomised measures of frailty (non-frail: CFS 1-4, frail: 5-8) and CFS as a continuous ordinal scale.
In 433 individuals with ischaemic stroke, 28-day mortality was higher in frail versus non-frail individuals (39 (16.7%) versus 10 (5%), P < 0.01). On multivariable analysis, a one-point increase in CFS was independently associated with 28-day mortality (OR 1.03 (1.01-1.05)). In 63 thrombolysed individuals, median NIHSS reduced significantly in non-frail individuals (12.5 (interquartile range (IQR) 9.25) to 5 (IQR 10.5), P < 0.01) but not in frail individuals (15 (IQR 11.5) to 16 (IQR 16.5), P = 0.23). On multivariable analysis, a one-point increase in CFS was independently associated with a one-point reduction in post-thrombolysis NIHSS improvement (coefficient 1.07, P = 0.03).
Clinical frailty is independently associated with 28-day mortality after ischaemic stroke and appears independently associated with attenuated improvement in NIHSS following stroke thrombolysis. Further research is needed to elucidate the underlying mechanisms and how frailty may be utilised in clinical decision-making.
Previous research suggests that various types of childhood maltreatment frequently co-occur and confer risk for multiple psychiatric diagnoses. This non-specific pattern of risk may mean that ...childhood maltreatment increases vulnerability to numerous specific psychiatric disorders through diverse, specific mechanisms or that childhood maltreatment engenders a generalised liability to dimensions of psychopathology. Although these competing explanations have different implications for intervention, they have never been evaluated empirically.
We used a latent variable approach to estimate the associations of childhood maltreatment with underlying dimensions of internalising and externalising psychopathology and with specific disorders after accounting for the latent dimensions. We also examined gender differences in these associations.
Data were drawn from a nationally representative survey of 34 653 US adults. Lifetime DSM-IV psychiatric disorders were assessed using the AUDADIS-IV. Physical, sexual and emotional abuse and neglect were assessed using validated measures. Analyses controlled for other childhood adversities and sociodemographics.
The effects were fully mediated through the latent liability dimensions, with an impact on underlying liability levels to internalising and externalising psychopathology rather than specific psychiatric disorders. Important gender differences emerged with physical abuse associated only with externalising liability in men, and only with internalising liability in women. Neglect was not significantly associated with latent liability levels.
The association between childhood maltreatment and common psychiatric disorders operates through latent liabilities to experience internalising and externalising psychopathology, indicating that the prevention of maltreatment may have a wide range of benefits in reducing the prevalence of many common mental disorders. Different forms of abuse have gender-specific consequences for the expression of internalising and externalising psychopathology, suggesting gender-specific aetiological pathways between maltreatment and psychopathology.
Cortical inhibition is mediated by diverse inhibitory neuron types that can each play distinct roles in information processing by virtue of differences in their input sources, intrinsic properties, ...and innervation targets. Previous studies in brain slices have demonstrated considerable cell-type specificity in laminar sources of local inputs. In contrast, little is known about possible differences in distant inputs to different cortical interneuron types. We used the monosynaptic rabies virus system, in conjunction with mice expressing Cre recombinase in either parvalbumin-positive, somatostatin-positive (SST+), or vasoactive intestinal peptide-positive (VIP+) neurons, to map the brain-wide input to the three major nonoverlapping classes of interneurons in mouse somatosensory cortex. We discovered that all three classes of interneurons received considerable input from known cortical and thalamic input sources, as well as from probable cholinergic cells in the basal nucleus of Meynert. Despite their common input sources, these classes differed in the proportion of long-distance cortical inputs originating from deep versus superficial layers. Similar to their laminar differences in local input, VIP+ neurons received inputs predominantly from deep layers while SST+ neurons received mostly superficial inputs. These classes also differed in the amount of input they received. Cortical and thalamic inputs were greatest onto VIP+ interneurons and smallest onto SST+ neurons.
These results indicate that all three major interneuron classes in the barrel cortex integrate both feedforward and feedback information from throughout the brain to modulate the activity of the local cortical circuit. However, differences in laminar sources and magnitude of distant cortical input suggest differential contributions from cortical areas. More input to vasoactive intestinal peptide-positive (VIP+) neurons than to somatostatin-positive (SST+) neurons suggests that disinhibition of the cortex via VIP+ cells, which inhibit SST+ cells, might be a general feature of long-distance corticocortical and thalamocortical circuits.
In the mouse, each class of olfactory receptor neurons expressing a given odorant receptor has convergent axonal projections to two specific glomeruli in the olfactory bulb, thereby creating an odour ...map. However, it is unclear how this map is represented in the olfactory cortex. Here we combine rabies-virus-dependent retrograde mono-trans-synaptic labelling with genetics to control the location, number and type of 'starter' cortical neurons, from which we trace their presynaptic neurons. We find that individual cortical neurons receive input from multiple mitral cells representing broadly distributed glomeruli. Different cortical areas represent the olfactory bulb input differently. For example, the cortical amygdala preferentially receives dorsal olfactory bulb input, whereas the piriform cortex samples the whole olfactory bulb without obvious bias. These differences probably reflect different functions of these cortical areas in mediating innate odour preference or associative memory. The trans-synaptic labelling method described here should be widely applicable to mapping connections throughout the mouse nervous system.
We describe a powerful system for revealing the direct monosynaptic inputs to specific cell types in Cre-expressing transgenic mice through the use of Cre-dependent helper virus and a modified rabies ...virus. We generated helper viruses that target gene expression to Cre-expressing cells, allowing us to control initial rabies virus infection and subsequent monosynaptic retrograde spread. Investigators can use this system to elucidate the connections onto a desired cell type in a high-throughput manner, limited only by the availability of Cre mouse lines. This method allows for identification of circuits that would be extremely tedious or impossible to study with other methods and can be used to build subcircuit maps of inputs onto many different types of cells within the same brain region. Furthermore, by expressing various transgenes from the rabies genome, this system also has the potential to allow manipulation of targeted neuronal circuits without perturbing neighboring cells.
The role of different amygdala nuclei (neuroanatomical subdivisions) in processing Pavlovian conditioned fear has been studied extensively, but the function of the heterogeneous neuronal subtypes ...within these nuclei remains poorly understood. Here we use molecular genetic approaches to map the functional connectivity of a subpopulation of GABA-containing neurons, located in the lateral subdivision of the central amygdala (CEl), which express protein kinase C-δ (PKC-δ). Channelrhodopsin-2-assisted circuit mapping in amygdala slices and cell-specific viral tracing indicate that PKC-δ(+) neurons inhibit output neurons in the medial central amygdala (CEm), and also make reciprocal inhibitory synapses with PKC-δ(-) neurons in CEl. Electrical silencing of PKC-δ(+) neurons in vivo suggests that they correspond to physiologically identified units that are inhibited by the conditioned stimulus, called CEl(off) units. This correspondence, together with behavioural data, defines an inhibitory microcircuit in CEl that gates CEm output to control the level of conditioned freezing.
Radiomics, quantitative feature extraction from radiological images, can improve disease diagnosis and prognostication. However, radiomic features are susceptible to image acquisition and ...segmentation variability. Ideally, only features robust to these variations would be incorporated into predictive models, for good generalisability. We extracted 93 radiomic features from carotid artery computed tomography angiograms of 41 patients with cerebrovascular events. We tested feature robustness to region-of-interest perturbations, image pre-processing settings and quantisation methods using both single- and multi-slice approaches. We assessed the ability of the most robust features to identify culprit and non-culprit arteries using several machine learning algorithms and report the average area under the curve (AUC) from five-fold cross validation. Multi-slice features were superior to single for producing robust radiomic features (67 vs. 61). The optimal image quantisation method used bin widths of 25 or 30. Incorporating our top 10 non-redundant robust radiomics features into ElasticNet achieved an AUC of 0.73 and accuracy of 69% (compared to carotid calcification alone AUC: 0.44, accuracy: 46%). Our results provide key information for introducing carotid CT radiomics into clinical practice. If validated prospectively, our robust carotid radiomic set could improve stroke prediction and target therapies to those at highest risk.
Drugs of abuse elicit powerful experiences that engage populations of neurons broadly distributed throughout the brain. To determine how synaptic connectivity is organized to enable robust ...communication between populations of drug-activated neurons, we developed a complementary targeting system for monosynaptic rabies virus (RV) tracing that identifies direct inputs to activated versus nonactivated neuronal populations. Analysis of over 100,000 synaptic input neurons demonstrated that cocaine-activated neurons comprise selectively connected but broadly distributed corticostriatal networks. Electrophysiological assays using optogenetics to stimulate activated versus nonactivated inputs revealed stronger synapses between coactivated cortical pyramidal neurons and neurons in the dorsal striatum (DS). Repeated cocaine exposure further enhanced the connectivity specifically between drug-activated neurons in the orbitofrontal cortex (OFC) and coactive DS neurons. Selective chemogenetic silencing of cocaine-activated OFC neurons or their terminals in the DS disrupted behavioral sensitization, demonstrating the utility of this methodology for identifying novel circuit elements that contribute to behavioral plasticity.
•Cre-ON and Cre-OFF vectors enable complementary targeting of rabies virus•Cocaine-activated neurons form brain-spanning networks with specialized synapses•Chronic cocaine further enhances connectivity between OFC and DS active neurons•Cocaine-activated OFC-to-DS projection regulates behavioral sensitization
Wall et al. demonstrate that a cocaine experience recruits diverse populations of cortical and dorsal striatal neurons into coherent, persistent ensembles with heightened synaptic transmission. Chronic cocaine induces pathway-specific circuit remodeling, which impacts the expression of a drug-related behavior.
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