Dendritic Domains Research Articles

A Spin–Orbit Torque Knob to Tailor Stochasticity for Physically Secured Applications

AbstractThe deterministic switching of spin–orbit torque (SOT) memory has long been the primary challenge for implementation. Conversely, stochastic switching has recently sparked significant interest for physically secured applications. This study investigates the effects of an external field (Hx) applied to break the SOT symmetry for deterministic switching in a Pt/Co bilayer with perpendicular anisotropy. This external field serves as a tuning mechanism to adjust the stochasticity at the intermediate state during SOT switching. It is observed that moderate Hx could lead to a substantial variation in electrical output during the repeating write/read operations. In contrast, a large Hx enables precise control over the intermediate states of the Pt/Co bilayer, effectively functioning as a memristor. The stochasticity derives from small Hx resulting from the dynamics of dendritic domain wall propagation during SOT switching. Herein, the oblique domain spiking from the initially reversed domain is notably influenced by the transverse component of SOT. Increasing Hx suppresses this oblique dendritic domain growth, allowing for controllable domain propagation and reducing stochasticity. By utilizing Hx as an external knob to tailor the stochasticity at the intermediate state, the high stochastic state can be employed as an ideal entropy source for an SOT‐based random number generator.

Delta opioid receptors engage multiple signaling cascades to differentially modulate prefrontal GABA release with input and target specificity.

Opioids regulate circuits associated with motivation and reward across the brain. Of the opioid receptor types, delta opioid receptors (DORs) appear to have a unique role in regulating the activity of circuits related to reward without a liability for abuse. In neocortex, DORs are expressed primarily in interneurons, including parvalbumin- and somatostatin-expressing interneurons that inhibit somatic and dendritic compartments of excitatory pyramidal cells, respectively. But how DORs regulate transmission from these key interneuron classes is unclear. We found that DORs regulate inhibition from these interneuron classes using different G-protein signaling pathways that both converge on presynaptic calcium channels, but regulate distinct aspects of calcium channel function. This imposes different temporal filtering effects, via short-term plasticity, that depend on how calcium channels are regulated. Thus, DORs engage differential signaling cascades to regulate inhibition depending on the postsynaptic target compartment, with different effects on synaptic information transfer in somatic and dendritic domains.

Structural changes shaping the Drosophila ellipsoid body ER-neurons during development and aging

The ellipsoid body (EB) of the insect brain performs pivotal functions in controlling navigation. Input and output of the EB is provided by multiple classes of R-neurons (now referred to as ER-neurons) and columnar neurons which interact with each other in a stereotypical and spatially highly ordered manner. The developmental mechanisms that control the connectivity and topography of EB neurons are largely unknown. One indispensable prerequisite to unravel these mechanisms is to document in detail the sequence of events that shape EB neurons during their development. In this study, we analyzed the development of the Drosophila EB. In addition to globally following the ER-neuron and columnar neuron (sub)classes in the spatial context of their changing environment we performed a single cell analysis using the multi-color flip out (MCFO) system to analyze the developmental trajectory of ER-neurons at different pupal stages, young adults (4d) and aged adults (∼60d). We show that the EB develops as a merger of two distinct elements, a posterior and anterior EB primordium (prEBp and prEBa, respectively. ER-neurons belonging to different subclasses form growth cones and filopodia that associate with the prEBp and prEBa in a pattern that, from early pupal stages onward, foreshadows their mature structure. Filopodia of all ER-subclasses are initially much longer than the dendritic and terminal axonal branches they give rise to, and are pruned back during late pupal stages. Interestingly, extraneous branches, particularly significant in the dendritic domain, are a hallmark of ER-neuron structure in aged brains. Aging is also associated with a decline in synaptic connectivity from columnar neurons, as well as upregulation of presynaptic protein (Brp) in ER-neurons. Our findings advance the EB (and ER-neurons) as a favorable system to visualize and quantify the development and age-related decline of a complex neuronal circuitry.

Clustered synapses develop in distinct dendritic domains in visual cortex before eye opening.

Synaptic inputs to cortical neurons are highly structured in adult sensory systems, such that neighboring synapses along dendrites are activated by similar stimuli. This organization of synaptic inputs, called synaptic clustering, is required for high-fidelity signal processing, and clustered synapses can already be observed before eye opening. However, how clustered inputs emerge during development is unknown. Here, we employed concurrent in vivo whole-cell patch-clamp and dendritic calcium imaging to map spontaneous synaptic inputs to dendrites of layer 2/3 neurons in the mouse primary visual cortex during the second postnatal week until eye opening. We found that the number of functional synapses and the frequency of transmission events increase several fold during this developmental period. At the beginning of the second postnatal week, synapses assemble specifically in confined dendritic segments, whereas other segments are devoid of synapses. By the end of the second postnatal week, just before eye opening, dendrites are almost entirely covered by domains of co-active synapses. Finally, co-activity with their neighbor synapses correlates with synaptic stabilization and potentiation. Thus, clustered synapses form in distinct functional domains presumably to equip dendrites with computational modules for high-capacity sensory processing when the eyes open.

Synaptic cell-adhesion molecule latrophilin-2 is differentially directed to dendritic domains of hippocampal neurons

Hippocampal pyramidal cells possess elaborate dendritic arbors with distinct domains that are targeted with input-specific synaptic sites. This synaptic arrangement is facilitated by synaptic cell-adhesion molecules that act as recognition elements to connect presynaptic and postsynaptic neurons. In this study, we investigate the organization of the synaptic recognition molecule latrophilin-2 at the surface of pyramidal neurons classified by spatial positioning and action potential firing patterns. Surveying two hippocampal neurons that highly express latrophilin-2, late-bursting CA1 pyramidal cells and early-bursting subiculum pyramidal cells, we found the molecule to be differentially positioned on their respective dendritic compartments. Investigating this latrophilin-2 positioning at the synaptic level, we found that the molecule is not present within either the pre- or postsynaptic terminal but rather is tightly coupled to synapses at a perisynaptic location. Together these findings indicate that hippocampal latrophilin-2 distribution patterning is cell-type specific, and requires multiple postsynaptic neurons for its synaptic localization.

Genetic context controls microglia‐induced neuronal damage in Alzheimer’s disease

AbstractBackgroundThe activation of microglia and the loss of synapses have emerged as key events in Alzheimer’s disease (AD) progression, yet the relationship between these processes is not clear. Previous studies suggest genetic variation controls microglial activation in AD mouse models, so we evaluated how the elimination of brain microglia influenced synapses on hippocampal pyramidal cells across two genetically distinct AD mouse models.MethodUsing a viral approach, we labeled hippocampal neurons that project to the frontal cortex by expressing GFP in young (3m) inbred C57BL/6J and genetically distinct PWK/PhJ female mice with or without a transgenic (APP/PS1) allele that drives amyloid pathology. At 4m we placed half of the mice on diet formulated with CSF1R inhibitor PLX5622 to deplete brain microglia. At 8m, a time when plaque pathology is present in transgenic mice, we examined cognition using the delayed spatial task. We then analyzed the density and morphology of spines across multiple dendritic domains, as well as amyloid plaques and markers of disease‐associated (DAM) and interferon responding (IRM) states of IBA1+ microglia.ResultWhile spatial cognition was unaffected by PLX5622, we identified B6.APP/PS1 as susceptible and PWK.APP/PS1 as resilient to cognitive deficits at 8m. Across both strains, PLX5622 depleted hippocampal microglia but did not affect amyloid plaques. In contrast, we observed strain differences in spine synapse density and morphology. Compared to spine stability across PWK wild‐type (WT) and APP/PS1 mice, we measured increased density of small spines in B6.APP/PS1 mice (compared to WT). B6.APP/PS1 mice showed reduced spine density with PLX5622, whereas PWK.APP/PS1 mice remained unaltered. These changes in spine density corresponded to DAM being resistant to depletion with PLX5622 in APP/PS1 mice (especially B6), whereas IRM were susceptible, suggesting a neuroprotective role for IRM.ConclusionWe show here that genetic context determines how synapses on CA1 projection neurons respond to the depletion of brain microglia and AD transgenes. Since PWK.APP/PS1 are resistant to hippocampal neuronal damage with robust microglia activation, this strain can be leveraged to further study mechanisms of resilience to AD cognitive deficits and neuropathological damage that can be harnessed for better AD therapeutic treatments.

Angular dependence of the magnetization relaxation in Co/Pt multilayers

We study the influence of defects in Co/Pt multilayers on the room-temperature magnetization reversal and relaxation mechanisms via angle-dependent magnetic viscosity and coercive field measurements. The data reveal a transition from pinning-dominated domain wall propagation to a sequence of pinning-dominated and uniform switching, with increasing tilt away from the normal direction. The leading role of the dendritic domain wall propagation in the nanogranular exchange-coupled films is corroborated by the scaling of relaxation times, the angular dependence of the coercive field, and Kerr microscopy.

Photoactivated Protein Degrader for Optical Control of Synaptic Function.

Hundreds of proteins determine the function of synapses, and synapses define the neuronal circuits that subserve myriad brain, cognitive, and behavioral functions. It is thus necessary to precisely manipulate specific proteins at specific sub-cellular locations and times to elucidate the roles of particular proteins and synapses in brain function. We developed PHOtochemically TArgeting Chimeras (PHOTACs) as a strategy to optically degrade specific proteins with high spatial and temporal precision. PHOTACs are small molecules that, upon wavelength-selective illumination, catalyze ubiquitylation and degradation of target proteins through endogenous proteasomes. Here, we describe the design and chemical properties of a PHOTAC that targets Ca2+/calmodulin-dependent protein kinase II alpha (CaMKIIα), which is abundant and crucial for the baseline synaptic function of excitatory neurons. We validate the PHOTAC strategy, showing that the CaMKIIα-PHOTAC is effective in mouse brain tissue. Light activation of CaMKIIα-PHOTAC removed CaMKIIα from regions of the mouse hippocampus only within 25 μm of the illuminated brain surface. The optically controlled degradation decreases synaptic function within minutes of light activation, measured by the light-initiated attenuation of evoked field excitatory postsynaptic potential (fEPSP) responses to physiological stimulation. The PHOTACs methodology should be broadly applicable to other key proteins implicated in synaptic function, especially for evaluating their precise roles in the maintenance of long-term potentiation and memory within subcellular dendritic domains.

Co-exposure to low-dose lead, cadmium, and mercury promotes memory deficits in rats: Insights from the dynamics of dendritic spine pruning in brain development

Lead (Pb), cadmium (Cd), and mercury (Hg) are environmentally toxic heavy metals that can be simultaneously detected at low levels in the blood of the general population. Although our previous studies have demonstrated neurodevelopmental toxicity upon co-exposure to these heavy metals at these low levels, the precise mechanisms remain largely unknown. Dendritic spines are the structural foundation of memory and undergo significant dynamic changes during development. This study focused on the dynamics of dendritic spines during brain development following Pb, Cd, and Hg co-exposure-induced memory impairment. First, the dynamic characteristics of dendritic spines in the prefrontal cortex were observed throughout the life cycle of normal rats. We observed that dendritic spines increased rapidly from birth to their peak value at weaning, followed by significant pruning and a decrease during adolescence. Dendritic spines tended to be stable until their loss in old age. Subsequently, a rat model of low-dose Pb, Cd, and Hg co-exposure from embryo to adolescence was established. The results showed that exposure to low doses of heavy metals equivalent to those detected in the blood of the general population impaired spatial memory and altered the dynamics of dendritic spine pruning from weaning to adolescence. Proteomic analysis of brain and blood samples suggested that differentially expressed proteins upon heavy metal exposure were enriched in dendritic spine-related cytoskeletal regulation and axon guidance signaling pathways and that cofilin was enriched in both of these pathways. Further experiments confirmed that heavy metal exposure altered actin cytoskeleton dynamics and disturbed the dendritic spine pruning-related LIM domain kinase 1-cofilin pathway in the rat prefrontal cortex. Our findings demonstrate that low-dose Pb, Cd, and Hg co-exposure may promote memory impairment by perturbing dendritic spine dynamics through dendritic spine pruning-related signaling pathways.

Influence of Surface Flows on the Shape of Fractal Domains.

Tidal breathing is associated with a 30% change of the surfactant-covered alveolar surface occurring about 16 times per minute. To model this highly dynamic process, erucic acid monolayers at the air-water interface were compressed fast. Brewster angle microscopy imaged the fractal liquid-condensed (LC) domains and quantified the surface flow in size, direction, and duration. Radial branch distribution of the domains has a minimum in the flow direction, as was shown with directionality histograms. The fast Fourier transform of the domains shows a preferential growth perpendicular to the flow direction. Additionally, at the beginning of the flow, the downstream side of the domain grows faster than the upstream side. Surface flows act on the mm to cm scale, cause an anisotropic flow in the liquid expanded phase surrounding the LC domain, and affect the overall domain shape. On the μm-scale, the dendritic or seaweed domains' branches were only slightly disturbed. These results may help to understand pulmonary surfactant layers.

Role of Hydrogen in Suppressing Secondary Nucleation in Chemical Vapor-Deposited MoS2

We investigate the ability of different carrier gases to control defects and secondary nucleation in atmospheric pressure chemical vapor deposition (APCVD) growth of MoS2 on Si/SiO2 substrates. We observe that a reducing environment using H2 gas is more favorable for achieving uniform two-dimensional (2D) growth. Compared to the growth in an inert environment, secondary nucleation on primary MoS2 domains grown using H2 as the carrier gas (H–MoS2) is drastically reduced. We employ a phase-field model to understand the role of enhanced surface diffusion in H–MoS2, due to passivation of defects and dangling bonds, promoting compact secondary domain formation as opposed to dendritic secondary domains under an inert environment. Using X-ray photoelectron spectroscopy, we show that the Mo(VI) oxidation state (corresponding to MoO3), which is prominent for MoS2 grown under an inert atmosphere, is highly suppressed in H–MoS2, leading to more pristine MoS2. This explains the superior electrical performance of H–MoS2 compared to those grown with other carrier gases. Our results offer a facile route to explore different growth environments to realize large-area true 2D films.

Laser deposited superalloys with rotated substrate orientations: Microstructures and single-crystal formation

One- and multi-layer laser powder depositions were performed on single crystal (SX) Ni-based superalloy DD6 by rotating the substrate orientation around the [100], [010], and [001] crystallographic directions with the angle ξ[hkl] (hkl = 100, 010, 001) from the initial orientation (001)/[100], and the substrate orientation effect on the microstructure and SX nature were determined. It shows that for the one-layer deposition, the substrates with different rotation manners produce various dendritic domain distributions and stray grain (SG) susceptibilities in the deposited bead. Remarkably, one epitaxial dendrite domain can be only obtained for the [010]-axis rotation with ξ[010] = ±45°, which can suppress the formation of SGs effectively. However, at least two dendrite domains exist for [100]- or [001]-axis rotations, leading to slight dependence of SG susceptibility on the orientation. The multi-layer deposition experiments reveal that the SX nature can be retained with ξ[010] = 45°. The underlying mechanism of the orientation-dependent SG susceptibility is that different substrate orientations cause various columnar-to-equiaxed transition (CET) sensitivities. The difference in SG susceptibility between laser deposition and laser remelting is also discussed. Our results can provide an in-depth insight into controlling SG via substrate orientation in the laser processed SX superalloy.

Phase transformations and magnetostriction in Fe100−xGax bulk alloys

Fe–Ga alloys, containing 18, 21, and 23 at.% of Ga, were prepared in bulk form. In their as-cast state, they display a small magnetostriction, that is strongly improved after annealing at 1000 °C for 24 h, and subsequent rapid cooling. Multiple characterization techniques, such as x-ray diffraction, differential scanning calorimetry, Mössbauer spectroscopy, temperature-dependent magnetization curves, hysteresis loops, magnetic force microscopy, and magnetostriction measurements, were exploited in synergy to gain a deep understanding of the structure–property relationships in the studied alloys, before and after annealing. The A2 phase, which is favored in the lower range of compositions and is promoted at the expense of the D03 one by annealing, is responsible for characteristic dendritic and maze magnetic domains, and for the strong improvement of the magnetostriction, which almost reaches 240 ppm (transverse configuration) in the alloys with 18 at.% of Ga, after annealing.

Repetitively burst-spiking neurons in reeler mice show conserved but also highly variable morphological features of layer Vb-fated "thick-tufted" pyramidal cells.

Reelin is a large extracellular glycoprotein that is secreted by Cajal-Retzius cells during embryonic development to regulate neuronal migration and cell proliferation but it also seems to regulate ion channel distribution and synaptic vesicle release properties of excitatory neurons well into adulthood. Mouse mutants with a compromised reelin signaling cascade show a highly disorganized neocortex but the basic connectional features of the displaced excitatory principal cells seem to be relatively intact. Very little is known, however, about the intrinsic electrophysiological and morphological properties of individual cells in the reeler cortex. Repetitive burst-spiking (RB) is a unique property of large, thick-tufted pyramidal cells of wild-type layer Vb exclusively, which project to several subcortical targets. In addition, they are known to possess sparse but far-reaching intracortical recurrent collaterals. Here, we compared the electrophysiological properties and morphological features of neurons in the reeler primary somatosensory cortex with those of wild-type controls. Whereas in wild-type mice, RB pyramidal cells were only detected in layer Vb, and the vast majority of reeler RB pyramidal cells were found in the superficial third of the cortical depth. There were no obvious differences in the intrinsic electrophysiological properties and basic morphological features (such as soma size or the number of dendrites) were also well preserved. However, the spatial orientation of the entire dendritic tree was highly variable in the reeler neocortex, whereas it was completely stereotyped in wild-type mice. It seems that basic quantitative features of layer Vb-fated RB pyramidal cells are well conserved in the highly disorganized mutant neocortex, whereas qualitative morphological features vary, possibly to properly orient toward the appropriate input pathways, which are known to show an atypical oblique path through the reeler cortex. The oblique dendritic orientation thus presumably reflects a re-orientation of dendritic input domains toward spatially highly disorganized afferent projections.

Aβ42 oligomers trigger synaptic loss through CAMKK2-AMPK-dependent effectors coordinating mitochondrial fission and mitophagy

During the early stages of Alzheimer’s disease (AD) in both mouse models and human patients, soluble forms of Amyloid-β 1–42 oligomers (Aβ42o) trigger loss of excitatory synapses (synaptotoxicity) in cortical and hippocampal pyramidal neurons (PNs) prior to the formation of insoluble amyloid plaques. In a transgenic AD mouse model, we observed a spatially restricted structural remodeling of mitochondria in the apical tufts of CA1 PNs dendrites corresponding to the dendritic domain where the earliest synaptic loss is detected in vivo. We also observed AMPK over-activation as well as increased fragmentation and loss of mitochondrial biomass in Ngn2-induced neurons derived from a new APPSwe/Swe knockin human ES cell line. We demonstrate that Aβ42o-dependent over-activation of the CAMKK2-AMPK kinase dyad mediates synaptic loss through coordinated phosphorylation of MFF-dependent mitochondrial fission and ULK2-dependent mitophagy. Our results uncover a unifying stress-response pathway causally linking Aβ42o-dependent structural remodeling of dendritic mitochondria to synaptic loss.

Seaweed and Dendritic Growth in Unsaturated Fatty Acid Monolayers.

The lateral movement in lipid membranes depends on their diffusion constant within the membrane. However, when the flux of the subphase is high, the convective flow beneath the membrane also influences lipid movement. Lipid monolayers of an unsaturated fatty acid at the water–air interface serve as model membranes. The formation of domains in the liquid/condensed coexistence region is investigated. The dimension of the domains is fractal, and they grow with a constant growth velocity. Increasing the compression speed of the monolayer induces a transition from seaweed growth to dendritic growth. Seaweed domains have broad tips and wide and variable side branch spacing. In contrast, dendritic domains have a higher fractal dimension, narrower tips, and small, well-defined side branch spacing. Additionally, the growth velocity is markedly larger for dendritic than seaweed growth. The domains’ growth velocity increases and the tip radius decreases with increasing supersaturation in the liquid/condensed coexistence region. Implications for membranes are discussed.

Learning binds new inputs into functional synaptic clusters via spinogenesis.

Learning induces the formation of new excitatory synapses in the form of dendritic spines, but their functional properties remain unknown. Here, using longitudinal in vivo two-photon imaging and correlated electron microscopy of dendritic spines in the motor cortex of mice during motor learning, we describe a framework for the formation, survival and resulting function of new, learning-related spines. Specifically, our data indicate that the formation of new spines during learning is guided by the potentiation of functionally clustered preexisting spines exhibiting task-related activity during earlier sessions of learning. We present evidence that this clustered potentiation induces the local outgrowth of multiple filopodia from the nearby dendrite, locally sampling the adjacent neuropil for potential axonal partners, likely via targeting preexisting presynaptic boutons. Successful connections are then selected for survival based on co-activity with nearby task-related spines, ensuring that the new spine preserves functional clustering. The resulting locally coherent activity of new spines signals the learned movement. Furthermore, we found that a majority of new spines synapse with axons previously unrepresented in these dendritic domains. Thus, learning involves the binding of new information streams into functional synaptic clusters to subserve learned behaviors.

Perspectives on Mechanisms Supporting Neuronal Polarity From Small Animals to Humans.

Axon-dendrite formation is a crucial milestone in the life history of neurons. During this process, historically referred as “the establishment of polarity,” newborn neurons undergo biochemical, morphological and functional transformations to generate the axonal and dendritic domains, which are the basis of neuronal wiring and connectivity. Since the implementation of primary cultures of rat hippocampal neurons by Gary Banker and Max Cowan in 1977, the community of neurobiologists has made significant achievements in decoding signals that trigger axo-dendritic specification. External and internal cues able to switch on/off signaling pathways controlling gene expression, protein stability, the assembly of the polarity complex (i.e., PAR3-PAR6-aPKC), cytoskeleton remodeling and vesicle trafficking contribute to shape the morphology of neurons. Currently, the culture of hippocampal neurons coexists with alternative model systems to study neuronal polarization in several species, from single-cell to whole-organisms. For instance, in vivo approaches using C. elegans and D. melanogaster, as well as in situ imaging in rodents, have refined our knowledge by incorporating new variables in the polarity equation, such as the influence of the tissue, glia-neuron interactions and three-dimensional development. Nowadays, we have the unique opportunity of studying neurons differentiated from human induced pluripotent stem cells (hiPSCs), and test hypotheses previously originated in small animals and propose new ones perhaps specific for humans. Thus, this article will attempt to review critical mechanisms controlling polarization compiled over decades, highlighting points to be considered in new experimental systems, such as hiPSC neurons and human brain organoids.

Dendritic Domain-Specific Sampling of Long-Range Axons Shapes Feedforward and Feedback Connectivity of L5 Neurons.

Feedforward and feedback pathways interact in specific dendritic domains to enable cognitive functions such as predictive processing and learning. Based on axonal projections, hierarchically lower areas are thought to form synapses primarily on dendrites in middle cortical layers, while higher-order areas are posited to target dendrites in layer 1 and in deep layers. However, the extent to which functional synapses form in regions of axo-dendritic overlap has not been extensively studied. Here, we use viral tracing in the secondary visual cortex of male mice to map brain-wide inputs to thick-tufted layer 5 pyramidal neurons. Furthermore, we provide a comprehensive map of input locations through subcellular optogenetic circuit mapping. We show that input pathways target distinct dendritic domains with far greater specificity than appears from their axonal branching, often deviating substantially from the canonical patterns. Common assumptions regarding the dendrite-level interaction of feedforward and feedback inputs may thus need revisiting.

Dendritic Architecture Predicts in vivo Firing Pattern in Mouse Ventral Tegmental Area and Substantia Nigra Dopaminergic Neurons.

The firing activity of ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) dopaminergic (DA) neurons is an important factor in shaping DA release and its role in motivated behavior. Dendrites in DA neurons are the main postsynaptic compartment and, along with cell body and axon initial segment, contribute to action potential generation and firing pattern. In this study, the organization of the dendritic domain in individual VTA and SNc DA neurons of adult male mice, and their relationship to in vivo spontaneous firing, are described. In comparison with dorsal VTA DA neurons, ventrally located VTA neurons (as measured by cell body location) possess a shorter total dendritic length and simpler dendritic architecture, and exhibit the most irregular in vivo firing patterns among DA neurons. In contrast, for DA neurons in the SNc, the higher irregularity of firing was related to a smaller dendritic domain, as measured by convex hull volumes. However, firing properties were also related to the specific regional distribution of the dendritic tree. Thus, VTA DA neurons with a larger extension of their dendritic tree within the parabrachial pigmented (PBP) nucleus fired more regularly compared with those with relatively more dendrites extending outside the PBP. For DA neurons in the SNc, enhanced firing irregularity was associated with a smaller proportion of dendrites penetrating the substantia nigra pars reticulata. These results suggest that differences in dendritic morphology contribute to the in vivo firing properties of individual DA neurons, and that the existence of region-specific synaptic connectivity rules that shape firing diversity.