At the turn of the twentieth century Cajal (1899, 2002) published what is considered now as the beginning of the modern anatomical understanding of the brain. Cajal’s work, entirely dependent on the Golgi staining method, analyzed the neuroanatomical circuitry of complete brains in multiple species. His work stands out from 100 years of subsequent research as a single comprehensive examination across species and brain regions. Brodmann (1909) and von Economo (1929) respectively produced what are, surprisingly still today, the most comprehensive cytoarchitectonic maps of the human cerebral cortex. By the early 1970s, axonal tracing methods were introduced to study distant neuroanatomical projections (Graham and Karnovsky, 1966; Kristensson and Olsson, 1971). Tracing studies have continued to improve and produce detailed projection and connectivity data, but in so doing, fragment knowledge across species and brain regions (Zaborszky et al., 2006).
Forming an accurate mental view of brain circuitry is difficult, yet without one we cannot understand the function of the brain. Only with a comprehensive and cohesive picture can we make accurate inferences about the function of discrete neuroanatomical circuits. Each structure imposes dependencies and constraints on any theory that must be maintained for a working hypothesis of brain function. Several efforts are currently underway to reconcile the disparity between individual connectivity studies within a global scope. CoCoMac, a tool based on primate literature, represents the state of the art in mapping corticocortical interconnectivity between functional regions (Kotter, 2004). The Human Connectome Project (Marcus et al., 2011), along with other projects within the NIH Blueprint for Neuroscience Research, are using novel imaging methods to describe connectivity details for both primate and human brains (Stephan et al., 2000; Schmahmann et al., 2007; Hagmann et al., 2010). Unfortunately the resolution of external imaging methods is insufficient to elucidate neuroanatomical details underlying circuit organization.
This review is an attempt to form a comprehensive and cohesive understanding of the primate non-primary neuroanatomical circuitry through consilience (the integration of knowledge). Our first goal is to assemble a comprehensive neuroanatomical picture that is not inconsistent with known facts. We have produced an interactive visualization by synthesizing a vast number of fragmented studies into a single referenced framework that can be explored dynamically (Figure 1). We present this neuroanatomical picture as a detailed first-order approximation of cognitive circuitry in the primate brain for use as a skeleton upon which to hang additional knowledge. The visualizations should be viewed as information static “interactive figures” associated with the review. The re-application of the technology and framework as an interactive tool with evolving information is a desirable future endeavor.
Figure 1. The comprehensive neuroanatomical picture formed by synthesizing hundreds of original neuroanatomical studies into the homotypical blueprint underlying cognition. The interactive visualization can be experienced at http://www.frontiersin.org/files/cognitiveconsilience/index.html. The visualization is designed to be interactively zoomable, therefore details may not be clear in the above image. The 6-layered cerebral isocortex with 9 distinct pyramidal neurons and 8 cortical interneurons is presented at the top with a Nissl background. The parahippocampal gyrus including upper (PH23) and lower (PH56) layers and the hippocampus including the dentate gyrus (Dg), CA3 fields, CA1 fields, and subiculum (Sb; green). The thalamus is divided into 4 parts namely the specific, intralaminar, layer 1 projecting and thalamic reticular nucleus (Trn; orange). The basal ganglia includes the matrix (D1 and D2 receptors) and patch portions of the striatum, the external globus pallidus (Gpe), the internal globus pallidus (Gpi) and substantia nigra pars reticulata (Snr), the subthalamic nucleus (Stn), and the substantia nigra pars compacta (Snc; blue). The metencephalon includes the pons, cerebellum, and deep cerebellar nuclei (Dcn; purple). Finally the spinal chord, claustrum, and basal forebrain are shown in black.
Our second goal is to synthesize the facts and patterns in the established neuroanatomical picture into a detailed functional framework consisting of seven discrete circuits that correspond to psychological perspectives on the brain. While neuroanatomy is necessary to understand the function of a brain, it is not sufficient. The vast amount of additional information from electrophysiology to psychology must be integrated and explained. For each circuit we provide a brief hypothesis of cognitive circuitry development and information flow at the neuron level. We understand that our novel functional perspective may generate healthy conversation and debate. The technology we provide offers an easily accessible medium in which to question, challenge, and verify the information presented.
Ultimately, cognitive consilience is an attempt to establish a unified framework within which the vast majority of knowledge on the primate brain can be placed.
2. Methods and Technology: Web, Iphone, and Ipad App
Methodologically, the interactive Figure 1 was created by performing an extensive review of the non-primary primate literature, organizing the knowledge into a single framework, and selecting relevant reference data to include on the graphic. Non-primate data was utilized in occasions where primate data was insufficient or did not exist. In order to be placed on the graphic, reference data needed to contain sufficiently detailed location information by identifying an afferent/efferent cortical layer or subcortical nuclei. The graphic contains 410 referenced data visualization points from 186 unique references. By no means does this visualization include the complete body of neuroanatomical literature, but rather creates a comprehensive basis as a starting point for reader investigation. Data from many high quality citations could not be included as the data (raw or processed) was provided with insufficient spatial context. In general, we can only be as precise as the data we are reviewing. The graphic was hand drawn and attempts to recreate a reasonably accurate visual feel for structures, neurons, and their connectivity. Prominent axonal pathways were then identified as circuits, shown in Figure 4, based on known correlates with psychological and neuroscience data to provided a theoretical framework within which to understand neuroanatomy.
The review is accompanied by the release of an interactive web application and a portable application for the Apple iPad and iPhone (search: cognitive consilience), illustrated in Figure 2. The interactive figure was built around a Google Maps-like interface to enable a reader to rapidly locate relevant citations. Each functional circuit discussed in the following sections can be toggled on and off to refine the presentation of important citations. Neurons and projections are directly referenced with appropriate links to PubMed and NeuroLex. The web application provides additional search tools, including citation filters by publication date, species, author last name, and keywords.
Figure 2. Cognitive consilience visualization deployment across three technology platforms. The visualizations are identical and function similarly across platforms. (A) Interactive web application showing easy access to reference information throughout the visualization (http://www.frontiersin.org/files/cognitiveconsilience/index.html). (B) Deployment as an iPad App. (C) Deployment as an iPhone App.
The interactive medium provides a means for readers to rapidly evaluate hypotheses made in this review and to construct new ideas from the organized citations. The technology is presented as an information static “interactive figure” accompanying this review. Source code for the web application and raw citation data are available upon request and source code for the iphone/ipad app is available through collaboration. A future version that incorporates data mining and interactive citation addition is at the planning stage.
The inclusion of a spatially referenced interactive visualization accompanying a scientific review is novel and establishes a desirable new feature for future presentations of neuroanatomical work.
3. Primate Non-Primary Homotypical Architecture
Our near exclusive focus on primate non-primary data is unique. Neuroscience literature is biased toward studying primary sensory cortex in non-primates. This bias is introduced by the cost of primate research combined with the desire to correlate anatomical findings with electrophysiology stimulus response experiments.
As described in this review, the non-primary primate brain appears to have a consistent homotypical organization. The non-primary isocortex contains important contrasting features not found in primary sensory koniocortex, yet general cortical organization, in nearly all neuroscience textbooks, is taught corresponding to koniocortical principles (Purves et al., 2004). Some examples of primate isocortical principles not found in koniocortex:
1. Specific thalamocortical projections target layer 3b often avoiding layer 4,
2. Lack of layer 4 spiny stellate cells,
3. Striatally projecting layer 5 neurons, and
4. Long corticocortical white matter projections including callosal projections.
If we are to understand the entire primate (human) brain, our understanding must be based on the correct neuroanatomy. In this paper, we focus on primate non-primary literature, and consciously avoid major discussion and citing of primary sensory literature. In so doing, we hope to establish a basis for the fundamental principles of brain circuit organization.
Brains follow general principles of development dictated by evolved gene expression patterns (Striedter, 2005; Watakabe et al., 2007); however, for any “rule” or general principle of organization, there can be found an exception to the rule. The described functional circuits are an attempt to elucidate the blueprint of the homotypical neuroanatomical architecture underlying cognition. When we refer to the blueprint of a homotypical architecture, we imply that the underlying neuronal organization and projection rules are the same across different regions of analogous nuclei. If a neuron type X sends its most dense projections to a target location Z and sends collateral projections to location Y, we would consider X → Z the first-order neuroanatomical architecture. In order to create a compact yet comprehensive picture, we focus on the homotypical first-order architecture of the cerebral cortex, thalamus, basal ganglia, and their interconnections. This first-order architecture creates a factually consistent starting point upon which to build.
If we assume that neuroanatomical organization defines function, then a homotypical architecture supports the conjecture that different locations of the same neuronal group, although processing different information modalities, processes the information in the similar manner. Our viewpoint is that the cerebral cortex, thalamus, and basal ganglia only perform a limited few cognitive information processing functions. Within a homotypical architecture, each functional circuit determines how information is processed while the differences between the afferent input of two analogous pathways define what information is processed.
4. Neuroanatomical Circuits
Seven hypothesized functional circuits are presented. The seven circuits described are consolidated long-term declarative memory, short-term declarative memory, working memory/information processing, behavioral memory selection, behavioral memory output, cognitive control, and cortical information flow regulation. Each circuit is described in terms of readily distinguishable neuronal groups including the cerebral isocortex (9 pyramidal neuronal groups), parahippocampal gyrus and hippocampus, thalamus (4 neuronal groups), basal ganglia (7 neuronal groups), metencephalon, claustrum, basal forebrain, and spinal chord.
For clarity, each major neuronal group represented in the graphic is placed into only one primary circuit for discussion. However, in a functioning brain, circuits interact, and a single neuronal group participates in multiple circuits. The anatomical details of each circuit, shown in Figures 1 and 4, are meant to be explored dynamically through the associated technology.
The organization of the review follows a pattern to enable the reader to more clearly distinguish between neuroanatomical fact and the authors synthesized viewpoint. A subsection titled “perspective” concludes each circuit description and presents hypotheses and a more speculative synthesized viewpoint. All other sections attempt to conform to the unbiased presentation of important published information. We also include a concise summarized author’s viewpoint on the function of each neuronal group following their neuroanatomical description indicated with “Viewpoint”: Historical notes, indicated as such, are interjected to explain the current state of thinking and reinvigorate important concepts that seem faded in the literature.
4.1. Consolidated Long-Term Declarative Memory: Corticocortical Circuit
The identification of declarative memory is adopted from Squire as referring to “the capacity for conscious recollection about facts and events” (Squire, 2004). We define long-term memory as that which is stored semi-permanently in the isocortex. Lesions of the isocortex or of white matter fiber tracts produce a wide variety of stereotypical cognitive deficits (Geschwind, 1965b; Penfield and Rasmussen, 1968). Two distinct long-term memory deficits arise when comparing cortical gray matter lesions to corticocortical white matter lesions, although human lesions are rarely isolated (Geschwind, 1965a; Schmahmann et al., 2008). Localized gray matter lesions result in a reduced capacity to recall and process domain specific information, often manifesting as a form of agnosia (i.e., loss of the ability to recognize). For example, the inability of humans to recognize faces with lesions to the fusiform face area or recognize motion with lesions to cortical area MT. White matter lesions result in subtly different deficits representative of a disconnection of information shared between separate cortical areas. For example, lesions to the arcuate fasciculus disconnect Wernicke’s area (speech comprehension) from Broca’s area (speech production) and result in deficits in speech repetition (Damasio and Damasio, 1980). In essence, although speech comprehension and production both independently remain intact, the associations between them have been severed. These two distinct forms of long-term memory exist within the interconnectivity of the cerebral cortex.
4.1.1. Cerebral cortex
The human cerebral cortex is a 2.5-mm thick sheet of tissue approximately 2400 cm2 (four 8.5 × 11 pieces of paper) in size folded up around the entire brain (Toro et al., 2008). The cerebral cortex consists of a homotypical six layer pattern of neuron density distribution (von Economo, 1929; Lorente de No, 1943). The cerebral cortex develops inside out, with neurons in the innermost layer (L6) migrating into place first and neurons in successive outer layers migrating into place later (Rakic, 1995). Cortical laminar differentiation lies along a very clear spectrum with input sensory cortex being the most laminated/granular and output motor cortex being the least laminated/granular (von Economo, 1929; see Figure 3C). The lamination gradient represents a major clue in functional organization. The cerebral cortex can be grouped into the isocortex (neocortex), allocortex (paleocortex), periallocortex, and koniocortex (primary vision, auditory, somatosensory, and granulous retrosplenial cortex) based on laminar differentiation and developmental origin. The koniocortices are based on the same underlying anatomical principles of six layers and have evolved additional structure for their more specific sensory roles (Northcutt and Kaas, 1995). The patterns of laminar differentiation have been used to parse the entire cerebral cortex into distinct areas often called Brodmann’s areas (Brodmann, 1909; Triarhou, 2007). A large amount of experimental evidence on the cerebral cortex, from lesion studies to electrophysiology to FMRI, point to localized cortical information processing modules on the order of a few mm2 (Szentagothai, 1975; Catani and ffytche, 2005). Each area appears to process a distinct type of information reflecting the external and internal perceptions/behaviors of the individual, such as visual objects, language, executive plans, or movements (Penfield and Rasmussen, 1968; Goldman-Rakic, 1996; Grafton et al., 1996; Tanaka, 2003). The what of cortical information processing is thus highly localized and modular. The neuroanatomical organization underlying these what regions follows a very homotypical blueprint, which drives a functional perspective that how information is processed throughout the cerebral cortex is the same.
Figure 3. Prediction of human laminar corticocortical projections. Synthesis of von Economo cortical laminar types and homotypical laminar corticocortical projections in the monkey. Lateral (A) and medial (B) view of human cortical regions colored to correspond to the five fundamental cortical types depicted in (C) with numbers corresponding to Brodmann’s areas. (C) Von Economo’s five fundamental human cortical lamination types (von Economo, 1929). 1 = purple, 2 = dark blue, 3 = green, 4 = orange, 5 = yellow. The laminar distribution in the human cerebral cortex can be identified along a smooth numerical gradient, where 5 corresponds to “input” granular koniocortex and 1 corresponds to “output” agranular cortex. Horizontal red lines highlight layer boundaries, with average human cortical thickness = 2.5 mm. (D) Rough prediction of human laminar corticocortical (origin/termination) projection percentages predicted by numerical difference of cortical types in (C). Dotted red = % neurons originating in upper layers 2, 3. Dotted blue = % neurons originating in lower layers 5, 6, and lesser 4. Solid red = % synaptic terminations in layers 1, 2, and lesser 3. Solid blue = % synaptic terminations in mid/lower layers 4, 5, and lesser 6. In general, “feedforward” = (dotted red/solid blue), “feedback” = (solid red/dotted blue). Example: A type 2 (blue origin) projecting to a type 4 (orange target) would have a difference of -2(feedback), and predict roughly 25% of the projections from type 2 would originate from neurons in upper layers 2, 3, and roughly 20% of synaptic terminations in the type 3 cortical area would terminate in middle/lower layers.
4.1.2. Intracortical circuit
Intracortical projections are horizontal corticocortical projections traveling within the gray matter of the cerebral cortex (Kritzer and Goldman-Rakic, 1995). Although all pyramidal neurons have connections within the cerebral cortex, the prominent source of distant intracortical projections arise mainly from pyramidal neurons within layers 2 and 3, and a sub-set of neurons in layers 5 and 6. The intracortical terminations of C3a and C3b pyramidal neurons are not distributed uniformly, but form patchy or stripe-like patterns of termination which comprise areas up to 20 mm2 in the monkey (de Lima et al., 1990; Levitt et al., 1993; Fujita and Fujita, 1996; Pucak et al., 1996). Neurons in each layer appear to project horizontally, then the stripe-like terminations (spaced a few 100 μm apart) arise out of vertical collaterals. The laminar specificity and development of these corticocortical striped projections is largely activity dependent (Price et al., 2006). In the monkey, 50% of pyramidal neuron synaptic contacts, within its local stripe (roughly its dendritic tree size), are onto GABAergic inhibitory neurons, while more than 90% of synaptic contacts outside a pyramidal neurons local stripe are onto other pyramidal neurons (Melchitzky et al., 2001). The intracortical organization is suggestive that a functional module (∼10s mm2) in the isocortex is much larger than the traditional cortical minicolumn (∼100s μm2; Buxhoeveden and Casanova, 2002; Mountcastle, 2003; Rockland and Ichinohe, 2004).
Viewpoint: Neuroanatomically, an organization appears to exist where cell assemblies form intracortically in functional modules within select layers to encode perceptions.
4.1.3. Intercortical circuit
Intercortical circuits involve the large white matter corticocortical fiber tracts of the brain (Schmahmann and Pandya, 2006). Fiber tracts connect multiple distant cortical areas and subcortical nuclei with a great deal of specificity. The topology of corticocortical projections are the primary focus of the Human Connectome Project and CoCoMac (Kotter, 2004; Marcus et al., 2011). Contralateral corticocortical projections tend to connect the same spatial regions on opposite sides of the brain, while ipsilateral connections often connect distant areas on the same side (Barbas et al., 2005a). Different populations of pyramidal neurons tend to project contralaterally (lower layer 3b) as opposed to ipsilaterally (upper layer 3a and layers 5/6; Soloway et al., 2002).
We introduce a data-driven prediction for laminar projections between any two cortical areas in the human brain (Figure 3). Today, no safe experimental technique is capable of verifying laminar projections in the human. Yet by connecting and integrating previously unconnected research we arrive at very precise hypothesis with significant functional consequences in the human brain.
The cytoarchitectonics of the human cerebral cortex, as determined by von Economo, show the laminar pattern of a given area of cortex can generally fit within one of five fundamental types of cortical structure Figure 3C (von Economo, 1929; Walker, 1940). The pattern of projections between two cortical areas, as determined by Barbas in the monkey, shows a pattern of neuron layer origin and layer termination based on the difference between the two types of cortices as shown in Figure 3D (Barbas, 1986; Rockland, 1992; Barbas and Rempel-Clower, 1997; Rempel-Clower and Barbas, 2000; Barbas et al., 2005b; Van Essen, 2005; Medalla and Barbas, 2006). When von Economo and Barbas’ research is aligned, as they are for the first time here, we arrive at rough laminar projection predictions between cortical areas in the human brain.
If a projection originates in a more granular (e.g., type 4, Figure 3-orange) cortical area and terminates in a less granular (e.g., type 3, Figure 3-green) cortical area, the cells of origin are predominantly in layer 3, while synaptic terminals are in layer 4 with collaterals in layers 5, 6 (feedforward projection). The majority of projections in the cerebral cortex are feedforward and originate in layers 2/3. If the projection is reversed, projection neurons reside mostly in layer 5, some in 6, and project to layers 1 and 2 with collaterals in layer 3 (feedback projection). In visual areas, this pattern of projections has been correlated with the functional hierarchy of the cortical area (Felleman and Van Essen, 1991). The neuroanatomical architecture of a given cortical region appears to be the predictor of its functional relationship to other cortical areas.
Historical note: Barbas does not mention or cite von Economo in her papers in conjunction with the five types of cortical laminar patterns. The five types of laminar patterns in the monkey originated in 1947 when von Bonin adopted/translated von Economo’s human work into the monkey (von Bonin and Bailey, 1947). Since that time, the correlation between humans and monkeys appears to have been lost in the literature. Figure 3 is designed to illustrate the correlation between the original von Economo human study and Barbas’ monkey experiments performed 60 years later. The correlation adds additional significance to Barbas’ original cortical projection research in the monkey (Barbas, 1986).
Viewpoint: Neuroanatomically, cell assembly to cell assembly associations form intercortically in a hierarchical layer dependent feedforward/feedback network.
4.1.4. Cortical pyramidal layer 4 cortically projecting – C4
Layer 4 is referred to as the inner granular layer, not for any particular cell type, but due to the visual appearance of small neurons stained in Nissl preparations. Layer 4, of all cortices, appears to be an input for feedforward type projections. In isocortex, layer 4 is the primary target of ipsilateral corticocortical feedforward cortical projections (Figure 3; DeFelipe et al., 1986; Felleman and Van Essen, 1991; Rockland, 1992; Barbas et al., 2005a; Medalla and Barbas, 2006). Since primary sensory koniocortex is the anatomically closest cortex to raw sensory input, other cortical areas can not provide feedforward input. Instead, in koniocortices, the specific thalamus provides the feedforward projection into layer 4. In primary motor cortex layer 4 is essentially non-existent, highlighting the diminished need for feedforward input to cortical areas involved in output behavior. The cortical pyramidal neurons in layer 4, C4, typically have a descending and an ascending axon that arborize locally (<1 mm; Kritzer and Goldman-Rakic, 1995). The ascending axon reaches all supragranular layers upward of layer 2. Descending axons do not prominently exit the cortex as with most other pyramidal cells.
Only in primary sensory areas, and especially in primary visual cortex, does layer 4 contain spiny stellate cells (Meyer et al., 1989). In all other parts of cortex, spiny stellate cells are non-existent or very rare, and instead small pyramidal cells along with interneurons compose the majority of cells in L4. Quoting Lund “There are no spiny stellate neurons in V2 in contrast to area V1 where they are the main neuron types of lamina 4” (Lund et al., 1981).
Viewpoint: Neuroanatomically, C4 appears to function as a corticocortical feedforward input system.
4.1.5. Cortical pyramidal layer 2 cortically projecting – C2
Layer 2 is referred to as the outer granular layer because of its similar granular structure as layer 4. The C2 neurons are small pyramidal neurons with local horizontal projections mostly to layer 2 and to layer 3 (Tanigawa et al., 1998; Soloway et al., 2002; Barbas et al., 2005a). Layer 2 is a primary target of ipsilateral feedback type cortical projections (Figure 3). The granular similarity of layer 2 to layer 4 implies a similar input architecture for feedback projections. C2 receives feedback input and propagates information horizontally and down to C3a and C3b, with upper layer 5 being the focus of infragranular projections (Kritzer and Goldman-Rakic, 1995).
Viewpoint: Neuroanatomically, C2 appears to function as corticocortical feedback input system.
4.1.6. Cortical pyramidal layer 3a cortically projecting – C3a
C3a pyramidal neurons, of typical pyramidal shape, are distinguishable from layer 2 in isocortex because of their increased size and sparsity. In layer 3a the distance of intracortical horizontal projections increase into stripe-like patches (Lund et al., 1993; Fujita and Fujita, 1996; Melchitzky et al., 2001). C3a cells often have long horizontal projections in lower layer 3b (Kritzer and Goldman-Rakic, 1995). C3a cells are the dominant source of intercortical projections to layer 4 of ipsilateral cortices (Figure 3; DeFelipe et al., 1986; Rockland, 1992; Barbas et al., 2005a; Medalla and Barbas, 2006).
Viewpoint: Neuroanatomically, C3a appears to function as a corticocortical feedforward output system.
4.1.7. Cortical pyramidal layer 5/6 cortically projecting – C56
Neurons in the lower layers of the cerebral cortex are the most diverse, but are differentiable based on the targets of their projections. We use the term C56 to group the cortical neurons in the infragranular layers of the isocortex that dominantly project corticocortically (de Lima et al., 1990; Tanigawa et al., 1998; Soloway et al., 2002). The C56 neurons often have a spindle shape and appear to lack major dendritic tufts above layer 5a (de Lima et al., 1990). The intracortical supragranular projections appear more extensive in layers 2 and 3a (Levitt et al., 1993), with distant horizontal projections in layers 5/6 (Tardif et al., 2007). The C56 group are the dominant source of intercortical projections to layer 1 and 2 of ipsilateral cortices (Figure 3; Rockland and Drash, 1996; Barbas et al., 2005a; Medalla and Barbas, 2006).
Viewpoint: Neuroanatomically, C56 appears to function as corticocortical feedback output system.
4.1.8. Cortical interneurons
Cortical interneurons utilize gamma-Aminobutyric acid (GABA) as an inhibitory neurotransmitter and have axonal arbors that do not exit to the white matter. The increase in cortical interneuron number and complexity of organization has long been cited by neuroanatomists as a standard feature of phylogenetic evolution, humans having the greatest number and complexity (Cajal, 2002). Interneuron organization is complex, requiring attempts to standardize terminology (Ascoli et al., 2008). Interneurons are usually first characterized by their morphology, axonal arborization, and specificity of projections. Second, interneurons are often further differentiated by calcium binding protein staining (parvalbumin, calbindin, and calretinin) and their physiological firing properties. In the human, interneurons arise developmentally from two unique genetic expression patterns corresponding to the dorsal forebrain, a cerebral cortex precursor, and the ventral forebrain, a thalamic precursor (Letinic et al., 2002). Dendritic and axonal arborization of all inhibitory neurons are less than a few 100 μm in the monkey (Lund and Lewis, 1993). Inhibitory interneurons are the only known cortical neurons to form gap junctions and typically form gap junctions between the same type of interneuron (Gibson et al., 1999; Hestrin and Galarreta, 2005). Gap junctions have the property of spreading inhibition and synchronizing firing. In general, inhibitory GABAergic neurons are biased toward the upper layers of cortex. For conceptual simplicity, the dominant classes of interneurons are summarized in six neuroanatomical groupings:
1. Basket cells form the majority of interneurons, named for the basket like shape of synapses they form around the soma of pyramidal neurons (Cajal, 2002). Basket cells are typically fast spiking, parvalbumin staining, soma targeting, and have their highest densities between middle layer 3 and upper layer 5 (Lund and Lewis, 1993; Zaitsev et al., 2005). Basket cells are often further differentiated by the size and or curvature of their often long (∼100s μm) horizontal axonal arborization (Lund et al., 1993; Zaitsev et al., 2009).
2. Chandelier cells are a class of axoaxonic parvalbumin inhibitory neurons which provide exclusive terminations on the initial axon segment of pyramidal neurons found mostly between layers 3 and 5 (Lund and Lewis, 1993; Conde et al., 1994; Defelipe et al., 1999). Named for the vertical chandelier look alike synaptic boutons.
3. Neurogliaform cells are small, express calbindin, and are found throughout all layers, but biased toward superficial layers with a tight dense plexus of axons (Lund and Lewis, 1993; Gabbott and Bacon, 1996; Zaitsev et al., 2005).
4. Martinotti cells express calbindin and are unique in that they send a vertically projecting axon that arborizes horizontally in layer 1 (Conde et al., 1994; Zaitsev et al., 2009).
5. Double bouquet cells express calretinin and have vertically projecting dendrites and axons that span across layers that are direct sources of inter-layer feedforward or feedback projections (Lund and Lewis, 1993; Conde et al., 1994; Zaitsev et al., 2009). Bi-tufted neurons have similar dendritic and axonal organization.
6. Cajal-Retzius cells are horizontally projecting interneurons found exclusively in layer 1 of the cerebral cortex and are the only cells found in layer 1 (Conde et al., 1994; Gabbott and Bacon, 1996; Cajal, 2002).
Viewpoint: Neuroanatomically, interneurons appear to synchronize information processing and facilitate excitatory competition through localized vertical and horizontal inhibitory projections enabling cortical information processing.
4.1.9. Perspective on long-term declarative memory
Our neuroanatomical perspective is that long-term memory has two distinct components, namely perceptions and associations that correlate with psychological deficits related to gray matter (intracortical) vs white matter (intercortical) lesions respectively. Perceptions are a form of encoding of information, while associations form relational interactions between perceptions.
Perceptions would be the result of the self-organization of different cell assemblies within a cortical module likely during prolonged (years in humans vs weeks in animals) developmental critical periods (Murphy et al., 2005). Hebb (1949) postulated that groups of neurons would form these single perceptual representations called cell assemblies. Some 56 years later, creative experiments are proving that true showing cell assembly formation in L2/3 of rat visual cortex (Yoshimura et al., 2005). The developmental temporal regulation of NMDA and GABA synaptic receptors appears to control plasticity and the formation of perceptual cell assembly representations in critical periods (Murphy et al., 2005). The long-term stability of these cell assemblies could be a direct result of the elimination of this plasticity, through for example the dramatic decrease in NMDA receptors. The spatial extent and laminar location of these cell assemblies would be defined by intracortical projections. Intracortical projections suggest that cell assemblies within a cortical module should form primarily between neurons in similar layers C3–C3, C56–C56 (Kritzer and Goldman-Rakic, 1995). Our locally distributed viewpoint of perceptions is consistent with electrophysiology evidence in the monkey (Tanaka, 2003; Tsao et al., 2006), but in direct competition with other distributed views of perceptual organization (Fuster, 2003).
The localized nature of inhibition in the cerebral cortex and the prominently local connections of excitatory pyramidal neurons onto inhibitory neurons creates an architecture sufficient for local cell assembly activity based competition. Cortical laminar organization should further aid in both the development and information processing regulation of input/output cell assembly functions.
Once perceptions stabilize within cortical modules, intercortical synaptic associations between those perceptions can form throughout life. The stability of an association would be determined by the direct corticocortical synaptic connections between the two perceptions. Presumably, if a direct corticocortical association is stable (say with fewer NMDA receptors) it would be very difficult or impossible to remove naturally. For example, the word “Brad” might exist as a stable representation in Wernicke’s area, while the visual perception of facial features may exist in the fusiform face area. The simultaneous perceptions of “Brad” and “the face of Brad” could happen at any time in a persons life and may or may not be important to associate. As a consequence, the ability to temporarily store short-term associations for later consolidation to corticocortical long-term memory is necessary for the selection of stable associations. Short-term memory would presumably require an independent neuroanatomical architecture.
4.2. Short-Term Declarative Memory: Cortico-Hippocampal-Cortical Circuit
Psychological access to declarative memory occurs on different time-scales. Neuroanatomical evidence suggests the short-term memory system operates independently of the long-term memory system. Short-term declarative memory is defined as the declarative memory which requires the parahippocampal gyrus (periallocortex) and hippocampal (allocortex) formations for recollection (Squire, 2004). In humans, short-term memory takes weeks to years to consolidate from the periallocortex to the isocortex, wherein declarative memory is consolidated long-term (Squire and Alvarez, 1995). The localization of short-term memory to the hippocampal regions was demonstrated in patient H.M. who had no short-term memory, but retained long-term consolidated memory and behavioral/procedural memory. Due to surgical lesions, H.M. was essentially left with no allocortex or periallocortex (Milner, 2005). We can conclude that the periallocortical and hippocampal circuits are necessary neuroanatomical structures through which short-term memory is formed and later consolidated into corticocortical long-term memory (Squire and Zola, 1996; Eichenbaum, 2000; Squire, 2004).
4.2.1. Parahippocampal gyrus/periallocortex – PH
The parahippocampal gyrus, also called periallocortex because of its transitional laminar structure between isocortex and allocortex, consists of the entorhinal and perirhinal cortices. A reciprocal topographic connectivity exists between association isocortices and periallocortices that are well mapped, but the actual specificity of laminar projections remains vague at best (Witter et al., 1989; Burwell, 2000; Lavenex et al., 2002). The periallocortex contains intralayer connectivity similar to regular isocortex with less laminar differentiation. The periallocortex is the neuronal interface between the isocortex and the hippocampus, since the isocortex does not typically project directly to the hippocampus. The afferent input and efferent output of the periallocortex can grossly be split into upper (PH23) and lower (PH56) layers respectively based on its projections with the isocortex and allocortex. To a lesser degree, the periallocortex receives subcortical input from the amygdala, claustrum, basal forebrain, thalamus, hypothalamus, and brainstem (Insausti et al., 1987).
• PH23 is used to describe the upper layers in the periallocortex that receive afferent projections from the isocortex (typically C3b; Witter et al., 1989). Input to PH23 is topographically organized and dominated by multimodal association isocortex (Burwell, 2000). PH23 sends efferent projections to the hippocampus.
• PH56 is used to describe the lower layers in the periallocortex that send efferent projections to the isocortex with origin/target laminar distributions similar to intercortical association projections (Figure 3; Witter et al., 1989). PH56 generally projects back topographically in a reciprocal manner to multimodal association isocortex (Lavenex et al., 2002). PH56 receives afferent projections from the hippocampus.
The aggregate evidence suggests that C3b (and some C56) cells project to PH23 and receive reciprocal projections back from the PH56 regions to which they projected, but far more detailed studies are necessary.
Viewpoint: Neuroanatomically, the periallocortex appears to facilitate medium-term storage of associations, temporally acting between short-term and long-term memory, capable of mapping source C3b representations to target C3b representations in the isocortex.
4.2.2. Cortical pyramidal layer 3b cortically projecting – C3b
Lower layer 3b in the isocortex is centrally located to be the hub of perceptual information processing in the cerebral cortex. The large pyramidal neurons located in the lower part of layer 3, just above the granular layer 4 could be included in multiple circuits including long-term memory, working memory/information processing, and behavior output. The C3b cells have the classic pyramidal neuron shape and are usually the second largest pyramidal neuron group next to C5p (Jones and Wise, 1977; Rempel-Clower and Barbas, 2000; Barbas et al., 2005a). The C3b intracortical projections involve some of the longest (many millimeters) gray matter projections in the cerebral cortex (Kritzer and Goldman-Rakic, 1995; Fujita and Fujita, 1996; DeFelipe, 1997). The horizontal projections form stripe-like vertical patches and have all the same qualities described in the C3a group.
In the isocortex, different populations of pyramidal neurons tend to project contralaterally as opposed to ipsilaterally. The contralateral projections arise mostly from C3b cells and target the spatially analogous region of cortex on the other side of the brain, while ipsilateral projections mainly arise from C3a and C56 (Soloway et al., 2002). The same C3b and C56 cells appear to be the dominant source of isocortex → periallocortex projections (Witter et al., 1989; Burwell, 2000), responsible for communicating representations in the isocortex to the hippocampus for association.
The C3b cells appear to preferentially stain for acetylcholine with C5p cells (Voytko et al., 1992; Hackett et al., 2001), and have been shown to have preferential connections with C5p cells (Thomson and Bannister, 1998; Briggs and Callaway, 2005). In the agranular primary motor cortex, all layers visually look like a combination of C3b and C5p cells of various sizes.
Historical note: In 1949, Lorente de No referred to the large cells above the granular layer as “star pyramids” and called the location “layer 4a” (Lorente de No, 1943). Today, the same cells are typically referred to as large pyramidal neurons in layer 3b. The usage of the terms “star” and “layer 4” to describe these cells appears to have caused subtle confusion throughout the years, including the target layer of specific thalamocortical projections. The confusion arises due to the modern descriptions of “stellate” cells in “layer 4α” or “4β” of primary visual cortex.
Viewpoint: Neuroanatomically, C3b appears to function as stable invariant perceptual representations in the cerebral cortex that are associated in short-term memory.
The hippocampus proper, called allocortex due to its lack of lamination and different appearance from isocortex, is a full circuit in and of itself (Amaral and Witter, 1989). The hippocampus is functionally dominated by the dentate gyrus (DG), CA3 fields, CA1 fields, and subiculum (Sb). A simplified feedforward picture shows the projection circuit loop as: isocortex → PH23 → Dentate Gyrus → CA3 → CA1 → Subiculum → PH56 → isocortex. Multiple feedback connections exist within this path (Amaral and Witter, 1989). The DG and olfactory bulb/subventricular zone are the only widely accepted brain structures consistently shown to contain adult neurogenesis (the new production of neurons) in the non-damaged primate brain (Gould, 2007). The hippocampus essentially receives all the same subcortical input as parahippocampal cortex described above (Amaral and Cowan, 1980).
Viewpoint: Neuroanatomically, the hippocampus appears to associate perceptions in the isocortex through mapped representations in periallocortex based upon emotional context.
4.2.4. Perspective on short-term declarative memory
Our neuroanatomical perspective on the perihippocampal cortex and hippocampus are that they function to temporarily store short-term associations between isocortical perceptions that can later be consolidated into direct corticocortical long-term memory associations. The subcortical input to the peri-/allocortex being part of the emotional system would imply that the creation of associations is largely influenced by emotional significance. The functional flow of short-term memory information would appear to involve (see also Figures 4 and 5):
Figure 4. Cognitive circuits as shown at http://www.frontiersin.org/files/cognitiveconsilience/index.html. Circuits from left to right. Orange: consolidated declarative long-term memory. Green: short-term declarative memory. Purple: working memory/Information processing. Blue: Behavioral memory action selection. Black: behavioral memory output. Red: cognitive control. Yellow: cortical information flow regulation. Arrow head type indicates neurotransmitter: solid arrow-glutamate, feather-GABA, flower-acetylcholine, reverse arrow-dopamine. See website and text for additional details.
Figure 5. Summary diagram of proposed flow of cognitive information. Seven of the circuits described in the text are shown to illustrate a summarized functional viewpoint of the hypothesized flow of information. Generally information flows from left to right through the color coded circuits. Circuit names and colors are represented at the top. Long-term memory is split into “perceptions” and “associations” as discussed in 4.1. Information flow details are describe in the text. Cortical neuron x (Cx), Parahippocampal gyrus (PH), Hippocampus (H), Specific thalamus (Ts), Layer 1 projecting thalamus (TL1), Intralaminar thalamus (Ti), Cerebellum (C), Striatum (S), External segment globus pallidus (Gpe), Internal segment globus pallidus (Gpi), Substantia nigra par reticulata (Snr), Basal forebrain (BF; note: the basal forebrain is placed in layer 1 to demonstrate the primary target of its projections).
• Association (cortical area A and B) – active C3b perceptions in area A and B → activation PH23 A and B → binding in hippocampus. Additionally, PH23 A and B → PH56 A and B activations.
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