Mieko Morishima

Recurrent Connection Patterns of Corticostriatal Pyramidal Cells in Frontal Cortex

Corticostriatal pyramidal cells are heterogeneous in the frontal cortex. Here, we show that subpopulations of corticostriatal neurons in the rat frontal cortex are selectively connected with each other based on their subcortical targets. Using paired recordings of retrogradely labeled cells, we investigated the synaptic connectivity between two projection cell types: those projecting to the pons [corticopontine (CPn) cell], often with collaterals to the striatum, and those projecting to both sides of the striatum but not to the pons [crossed corticostriatal (CCS) cell]. The two types were morphologically differentiated in regard to their apical tufts. The dendritic morphologies of CCS cells were correlated with their somatic depth within the cortex. CCS cells had reciprocal synaptic connections with each other and also provided synaptic input to CPn cells. However, connections from CPn to CCS cells were rarely found, even in pairs showing CCS to CPn connectivity. Additionally, CCS cells preferentially innervated the basal dendrites of other CCS cells but made contacts onto both the basal and apical dendrites of CPn cells. The amplitude of synaptic responses was to some extent correlated with the contact site number. Ratios of the EPSC amplitude to the contact number tended to be larger in the CCS to CCS connection. Therefore, our data demonstrate that these two types of corticostriatal cells distinct in their dendritic morphologies show directional and domain-dependent preferences in their synaptic connectivity.

Selective Coexpression of Multiple Chemical Markers Defines Discrete Populations of Neocortical GABAergic Neurons

Whether neocortical γ-aminobutyric acid (GABA) cells are composed of a limited number of distinct classes of neuron, or whether they are continuously differentiated with much higher diversity, remains a contentious issue for the field. Most GABA cells of rat frontal cortex have at least 1 of 6 chemical markers (parvalbumin, calretinin, alpha-actinin-2, somatostatin, vasoactive intestinal polypeptide, and cholecystokinin), with each chemical class comprising several distinct neuronal subtypes having specific physiological and morphological characteristics. To better clarify GABAergic neuron diversity, we assessed the colocalization of these 6 chemical markers with corticotropin-releasing factor (CRF), neuropeptide Y (NPY), the substance P receptor (SPR), and nitric oxide synthase (NOS); these 4 additional chemical markers suggested to be expressed diversely or specifically among cortical GABA cells. We further correlated morphological and physiological characteristics of identified some chemical subclasses of inhibitory neurons. Our results reveal expression specificity of CRF, NPY, SPR, and NOS in morphologically and physiologically distinct interneuron classes. These observations support the existence of a limited number of functionally distinct subtypes of GABA cells in the neocortex.

Highly Differentiated Projection-Specific Cortical Subnetworks

Pyramidal cells in the neocortex are differentiated into several subgroups based on their extracortical projection targets. However, little is known regarding the relative intracortical connectivity of pyramidal neurons specialized for these specific output channels. We used paired recordings and quantitative morphological analysis to reveal distinct synaptic transmission properties, connection patterns, and morphological differentiation correlated with heterogeneous thalamic input to two different groups of pyramidal cells residing in layer 5 (L5) of rat frontal cortex. Retrograde tracers were used to label two projection subtypes in L5: crossed-corticostriatal (CCS) cells projecting to both sides of the striatum, and corticopontine (CPn) cells projecting to the ipsilateral pons. Although CPn/CPn and CCS/CCS pairs had similar connection probabilities, CPn/CPn pairs exhibited greater reciprocal connectivity, stronger unitary synaptic transmission, and more facilitation of paired-pulse responses. These synaptic characteristics were strongly correlated to the projection subtype of the presynaptic neuron. CPn and CCS cells were further differentiated according to their somatic position (L5a and L5b, the latter denser thalamic afferent fibers) and their dendritic/axonal arborizations. Together, our data demonstrate that the pyramidal projection system is segregated into different output channels according to subcortical target and thalamic input, and that information flow within and between these channels is selectively organized.

Reinforcement learning: computing the temporal difference of values via distinct corticostriatal pathways

Midbrain dopamine neurons supposedly encode reward prediction error, but how error signals are computed remains elusive. Here, we propose a mechanism based on recent findings regarding corticostriatal circuits. Specifically, we propose that two distinct subpopulations of corticostriatal neurons differentially represent the animals current and previous states/actions through unidirectional connectivity from one subpopulation to the other and strong recurrent excitation that exists only within the recipient subpopulation. These corticostriatal subpopulations selectively connect to the direct and indirect pathways of the basal ganglia, such that the temporal difference between the values of current and previous states/actions--the core of the error signal--can be computed. Our hypothesis suggests a unified view of basal ganglia functions and has important clinical implications.

Specialized Cortical Subnetworks Differentially Connect Frontal Cortex to Parahippocampal Areas

How information is manipulated and segregated within local circuits in the frontal cortex remains mysterious, in part because of inadequate knowledge regarding the connectivity of diverse pyramidal cell subtypes. The frontal cortex participates in the formation and retrieval of declarative memories through projections to the perirhinal cortex, and in procedural learning through projections to the striatum/pontine nuclei. In rat frontal cortex, we identified two pyramidal cell subtypes selectively projecting to distinct subregions of perirhinal cortex (PRC). PRC-projecting cells in upper layer 2/3 (L2/3) of the frontal cortex projected to perirhinal area 35, while neurons in L5 innervated perirhinal area 36. L2/3 PRC-projecting cells partially overlapped with those projecting to the basolateral amygdala. L5 PRC-projecting cells partially overlapped with crossed corticostriatal cells, but were distinct from neighboring corticothalamic (CTh)/corticopontine cells. L5 PRC-projecting and CTh cells were different in their electrophysiological properties and dendritic/axonal morphologies. Within the frontal cortex, L2/3 PRC-projecting cells innervated L5 PRC-projecting and CTh cells with similar probabilities, but received feedback excitation only from PRC-projecting cells. These data suggest that specific neuron subtypes in different cortical layers are reciprocally excited via interlaminar loops. Thus, two interacting output channels send information from the frontal cortex to different hierarchical stages of the parahippocampal network, areas 35 and 36, with additional collaterals selectively targeting the amygdala or basal ganglia, respectively. Combined with the hierarchical connectivity of PRC-projecting and CTh cells, these observations demonstrate an exquisite diversification of frontal projection neurons selectively connected according to their participation in distinct memory subsystems.

Dopaminergic Control of Motivation and Reinforcement Learning: A Closed-Circuit Account for Reward-Oriented Behavior

Humans and animals take actions quickly when they expect that the actions lead to reward, reflecting their motivation. Injection of dopamine receptor antagonists into the striatum has been shown to slow such reward-seeking behavior, suggesting that dopamine is involved in the control of motivational processes. Meanwhile, neurophysiological studies have revealed that phasic response of dopamine neurons appears to represent reward prediction error, indicating that dopamine plays central roles in reinforcement learning. However, previous attempts to elucidate the mechanisms of these dopaminergic controls have not fully explained how the motivational and learning aspects are related and whether they can be understood by the way the activity of dopamine neurons itself is controlled by their upstream circuitries. To address this issue, we constructed a closed-circuit model of the corticobasal ganglia system based on recent findings regarding intracortical and corticostriatal circuit architectures. Simulations show that the model could reproduce the observed distinct motivational effects of D1- and D2-type dopamine receptor antagonists. Simultaneously, our model successfully explains the dopaminergic representation of reward prediction error as observed in behaving animals during learning tasks and could also explain distinct choice biases induced by optogenetic stimulation of the D1 and D2 receptor-expressing striatal neurons. These results indicate that the suggested roles of dopamine in motivational control and reinforcement learning can be understood in a unified manner through a notion that the indirect pathway of the basal ganglia represents the value of states/actions at a previous time point, an empirically driven key assumption of our model.

Segregated Excitatory–Inhibitory Recurrent Subnetworks in Layer 5 of the Rat Frontal Cortex

Abstract A prominent feature of neocortical pyramidal cells (PCs) is their numerous projections to diverse brain areas. In layer 5 (L5) of the rat frontal cortex, there are 2 major subtypes of PCs that differ in their long‐range axonal projections, corticopontine (CPn) cells and crossed corticostriatal (CCS) cells. The outputs of these L5 PCs can be regulated by feedback inhibition from neighboring cortical GABAergic cells. Two major subtypes of GABAergic cells are parvalbumin (PV)‐positive and somatostatin (SOM)‐positive cells. PV cells have a fast‐spiking (FS) firing pattern, while SOM cells have a low threshold spike (LTS) and regular spiking. In this study, we found that the 2 PC subtypes in L5 selectively make recurrent connections with LTS cells. The connection patterns correlated with the morphological and physiological diversity of LTS cells. LTS cells with high input resistance (Ri) exhibited more compact dendrites and more rebound spikes than LTS cells with low Ri, which had vertically elongated dendrites. LTS subgroups differently inhibited the PC subtypes, although FS cells made nonselective connections with both projection subtypes. These results demonstrate a novel recurrent network of inhibitory and projection‐specific excitatory neurons within the neocortex.

Specialized Subpopulations of Deep-Layer Pyramidal Neurons in the Neocortex: Bridging Cellular Properties to Functional Consequences

Neocortical pyramidal neurons with somata in layers 5 and 6 are among the most visually striking and enigmatic neurons in the brain. These deep-layer pyramidal neurons (DLPNs) integrate a plethora of cortical and extracortical synaptic inputs along their impressive dendritic arbors. The pattern of cortical output to both local and long-distance targets is sculpted by the unique physiological properties of specific DLPN subpopulations. Here we revisit two broad DLPN subpopulations: those that send their axons within the telencephalon (intratelencephalic neurons) and those that project to additional target areas outside the telencephalon (extratelencephalic neurons). While neuroscientists across many subdisciplines have characterized the intrinsic and synaptic physiological properties of DLPN subpopulations, our increasing ability to selectively target and manipulate these output neuron subtypes advances our understanding of their distinct functional contributions. This Viewpoints article summarizes our current knowledge about DLPNs and highlights recent work elucidating the functional differences between DLPN subpopulations.

Reinforcement Learning: Computing the Temporal Difference of Values via Distinct Corticostriatal Pathways: (Trends in Neurosciences 35, 457–467; 2012)

The authors regret that they mischaracterized the composition of two cell populations in the ventral tegmental area (VTA) in the discussion within Box 1 of the original article. We would like to correct the following sentence on page 465, Box 1. Outstanding Questions. First bullet point under the heading “Reward prediction error signals in different regions”:“Dopamine neurons in the VTA have also been suggested to represent TD error [3,6,7,9]. We speculate that the two populations of VTA GABAergic cells…” should read: “Dopamine neurons in the VTA have also been suggested to represent TD error [3,6,7,9]. We speculate that the two populations of VTA cells (GABAergic and unidentified)…”The authors apologize for any inconvenience this has caused.