Subgenual and Hippocampal Pathways in Amygdala Are Set to Balance Affect and Context Processing.

The amygdala, hippocampus, and subgenual cortex area 25 (A25) are engaged in complex cognitive-emotional processes. Yet pathway interactions from hippocampus and A25 with postsynaptic sites in amygdala remain largely unknown. In rhesus monkeys of both sexes, we studied with neural tracers how pathways from A25 and hippocampus interface with excitatory and inhibitory microcircuits in amygdala at multiple scales. We found that both hippocampus and A25 innervate distinct as well as overlapping sites of the basolateral (BL) amygdalar nucleus. Unique hippocampal pathways heavily innervated the intrinsic paralaminar basolateral nucleus, which is associated with plasticity. In contrast, orbital A25 preferentially innervated another intrinsic network, the intercalated masses, an inhibitory reticulum that gates amygdalar autonomic output and inhibits fear-related behaviors. Finally, using high-resolution confocal and electron microscopy (EM), we found that among inhibitory postsynaptic targets in BL, both hippocampal and A25 pathways preferentially formed synapses with calretinin (CR) neurons, which are known for disinhibition and may enhance excitatory drive in the amygdala. Among other inhibitory postsynaptic sites, A25 pathways innervated the powerful parvalbumin (PV) neurons which may flexibly regulate the gain of neuronal assemblies in the BL that affect the internal state. In contrast, hippocampal pathways innervated calbindin (CB) inhibitory neurons, which modulate specific excitatory inputs for processing context and learning correct associations. Common and unique patterns of innervation in amygdala by hippocampus and A25 have implications for how complex cognitive and emotional processes may be selectively disrupted in psychiatric disorders.SIGNIFICANCE STATEMENT The hippocampus, subgenual A25, and amygdala are associated with learning, memory, and emotions. We found that A25 is poised to affect diverse amygdalar processes, from emotional expression to fear learning by innervating the basal complex and the intrinsic intercalated masses. Hippocampal pathways uniquely interacted with another intrinsic amygdalar nucleus which is associated with plasticity, suggesting flexible processing of signals in context for learning. In the basolateral (BL) amygdala, which has a role in fear learning, both hippocampal and A25 interacted preferentially with disinhibitory neurons, suggesting a boost in excitation. The two pathways diverged in innervating other classes of inhibitory neurons, suggesting circuit specificities that could become perturbed in psychiatric diseases.

Amygdalar Excitation of Hippocampal Interneurons Can Lead to Emotion-driven Overgeneralization of Context.

Context is central to cognition: Detailed contextual representations enable flexible adjustment of behavior via comparison of the current situation with prior experience. Emotional experiences can greatly enhance contextual memory. However, sufficiently intense emotional signals can have the opposite effect, leading to weaker or less specific memories. How can emotional signals have such intensity-dependent effects? A plausible mechanistic account has emerged from recent anatomical data on the impact of the amygdala on the hippocampus in primates. In hippocampal CA3, the amygdala formed potent synapses on pyramidal neurons, calretinin (CR) interneurons, as well as parvalbumin (PV) interneurons. CR interneurons are known to disinhibit pyramidal neuron dendrites, whereas PV neurons provide strong perisomatic inhibition. This potentially counterintuitive connectivity, enabling amygdala to both enhance and inhibit CA3 activity, may provide a mechanism that can boost or suppress memory in an intensity-dependent way. To investigate this possibility, we simulated this connectivity pattern in a spiking network model. Our simulations revealed that moderate amygdala input can enrich CA3 representations of context through disinhibition via CR interneurons, but strong amygdalar input can impoverish CA3 activity through simultaneous excitation and feedforward inhibition via PV interneurons. Our model revealed an elegant circuit mechanism that mediates an affective "inverted U" phenomenonv: There is an optimal level of amygdalar input that enriches hippocampal context representations, but on either side of this zone, representations are impoverished. This circuit mechanism helps explain why excessive emotional arousal can disrupt contextual memory and lead to overgeneralization, as seen in severe anxiety and posttraumatic stress disorder.

The analysis of H.M.'s brain: A brief review of status and plans for future studies and tissue archive.

The famous amnesic patient Henry Molaison (H.M.) died on December 2, 2008. After extensive in situ magnetic resonance imaging in Boston, his brain was removed at autopsy and transported to the University of California San Diego. There the brain was prepared for frozen sectioning and cut into 2401, 70 µm coronal slices. While preliminary analyses of the brain sections have been reported, a comprehensive microscopic neuroanatomical analysis of the state of H.M.'s brain at the time of his death has not yet been published. The brain tissue and slides were subsequently moved to the University of California Davis and the slides digitized at high resolution. Initial stages of producing a website for the public viewing of the images were also carried out. Recently, the slides, digital images, and tissue have been transferred to Boston University for permanent archiving. A new steering committee has been established and plans are in place for completion of a freely accessible H.M. website. Research publications on the microscopic anatomy and neuropathology of H.M.'s brain at the time of his death are also planned. We write this commentary to provide the hippocampus and memory neuroscience communities with a brief summary of what has transpired following H.M.'s death and outline plans for future publications and a tissue archive.

Pathways for Memory, Cognition and Emotional Context: Hippocampal, Subgenual Area 25, and Amygdalar Axons Show Unique Interactions in the Primate Thalamic Reuniens Nucleus.

The reuniens nucleus (RE) is situated at the most ventral position of the midline thalamus. In rats and mice RE is distinguished by bidirectional connections with the hippocampus and medial prefrontal cortex (mPFC) and a role in memory and cognition. In primates, many foundational questions pertaining to RE remain unresolved. We addressed these issues by investigating the composition of the rhesus monkey RE in both sexes by labeling for GABA, a marker of inhibitory neurons, and for the calcium-binding proteins parvalbumin (PV), calbindin (CB), and calretinin (CR), which label thalamic excitatory neurons that project to cortex. As in rats and mice, the macaque RE was mostly populated by CB and CR neurons, characteristic of matrix-dominant nuclei, and had bidirectional connections with hippocampus and mPFC area 25 (A25). Unlike rodents, we found GABAergic neurons in the monkey RE and a sparser but consistent population of core-associated thalamocortical PV neurons. RE had stronger connections with the basal amygdalar complex than in rats or mice. Amygdalar terminations were enriched with mitochondria and frequently formed successive synapses with the same postsynaptic structures, suggesting an active and robust pathway to RE. Significantly, hippocampal pathways formed multisynaptic complexes that uniquely involved excitatory projection neurons and dendrites of local inhibitory neurons in RE, extending this synaptic principle beyond sensory to high-order thalamic nuclei. Convergent pathways from hippocampus, A25, and amygdala in RE position it to flexibly coordinate activity for memory, cognition, and emotional context, which are disrupted in several psychiatric and neurologic diseases in humans.SIGNIFICANCE STATEMENT The primate RE is a central node for memory and cognition through connections with the hippocampus and mPFC. As in rats or mice, the primate RE is a matrix-dominant thalamic nucleus, suggesting signal traffic to the upper cortical layers. Unlike rats or mice, the primate RE contains inhibitory neurons, synaptic specializations with the hippocampal pathway, and robust connections with the amygdala, suggesting unique adaptations. Convergence of hippocampal, mPFC, and amygdalar pathways in RE may help unravel a circuit basis for binding diverse signals for conscious flexible behaviors and the synthesis of memory with affective significance in primates, whereas disruption of distinct circuit nodes may occur in psychiatric disorders in humans.

General cortical and special prefrontal connections: principles from structure to function.

How is the vast brain communication system organized? A structural model relates connections to laminar differences between linked areas. The model is based on the principle of systematic structural variation in the cortex, extending from the simplest limbic cortices to eulaminate areas with elaborate lamination. The model accounts for laminar patterns and for the strength and topography of connections between nearby or distant cortices and subcortical structures, exemplified quantitatively for the principal and special prefrontal connections. Widespread connections of limbic areas and focal connections of eulaminate areas yield a broad range of circuit patterns for diverse functions. These diverse pathways innervate excitatory and functionally distinct inhibitory neurons, providing the basis for differential recruitment of areas for flexible behavior. Systematic structural variation likely emerges by timing differences in the development of distinct areas and has important implications for altered connections in diseases of developmental origin.

Organization of primate amygdalar-thalamic pathways for emotions.

Studies on the thalamus have mostly focused on sensory relay nuclei, but the organization of pathways associated with emotions is not well understood. We addressed this issue by testing the hypothesis that the primate amygdala acts, in part, like a sensory structure for the affective import of stimuli and conveys this information to the mediodorsal thalamic nucleus, magnocellular part (MDmc). We found that primate sensory cortices innervate amygdalar sites that project to the MDmc, which projects to the orbitofrontal cortex. As in sensory thalamic systems, large amygdalar terminals innervated excitatory relay and inhibitory neurons in the MDmc that facilitate faithful transmission to the cortex. The amygdala, however, uniquely innervated a few MDmc neurons by surrounding and isolating large segments of their proximal dendrites, as revealed by three-dimensional high-resolution reconstruction. Physiologic studies have shown that large axon terminals are found in pathways issued from motor systems that innervate other brain centers to help distinguish self-initiated from other movements. By analogy, the amygdalar pathway to the MDmc may convey signals forwarded to the orbitofrontal cortex to monitor and update the status of the environment in processes deranged in schizophrenia, resulting in attribution of thoughts and actions to external sources.

Pathways for Contextual Memory: The Primate Hippocampal Pathway to Anterior Cingulate Cortex.

The anterior cingulate cortex (ACC) is one of the few prefrontal areas that receives robust direct hippocampal terminations. This pathway may enable current context and past experience to influence goal-directed actions and emotional regulation by prefrontal cortices. We investigated the still ill-understood organization of the pathway from anterior hippocampus to ACC (A24a, A25, A32) to identify laminar termination patterns and their postsynaptic excitatory and inhibitory targets from system to synapse in rhesus monkeys. The densest hippocampal terminations targeted posterior A25, a region that is involved in affective and autonomic regulation. Hippocampal terminations innervated mostly excitatory neurons (~90%), suggesting strong excitatory effects. Among the smaller fraction of inhibitory targets, hippocampal terminations in A25 preferentially innervated calretinin neurons, a pattern that differs markedly from rodents. Further, hippocampal terminations innervated spines with D1 receptors, particularly in the deep layers of A25, where D1 receptors are enriched in comparison with the upper layers. The proximity of hippocampal terminations to D1 receptors may enable dopamine to enhance information transfer from the hippocampus to A25 and contribute to dopaminergic influence downstream on goal-directed action and emotional control by prefrontal cortices, in processes that may be disrupted by excessive dopamine release during uncontrollable stress.

Serial Prefrontal Pathways Are Positioned to Balance Cognition and Emotion in Primates.

The delicate balance among primate prefrontal networks is necessary for homeostasis and behavioral flexibility. Dorsolateral prefrontal cortex (dlPFC) is associated with cognition, while the most ventromedial subgenual cingulate area 25 (A25) is associated with emotion and emotional expression. Yet A25 is weakly connected with dlPFC, and it is unknown how the two regions communicate. In rhesus monkeys of both sexes, we investigated how these functionally distinct areas may interact through pregenual anterior cingulate area 32 (A32), which is strongly connected with both. We found that dlPFC innervated the deep layers of A32, while A32 innervated all layers of A25, mostly targeting spines of excitatory neurons. Approximately 20% of A32 terminations formed synapses on inhibitory neurons in A25, notably the powerful parvalbumin inhibitory neurons in the deep layers, and the disinhibitory calretinin neurons in the superficial layers. By innervating distinct inhibitory microenvironments in laminar compartments, A32 is positioned to tune activity in columns of A25. The circuitry of the sequential pathway indicates that when dlPFC is engaged, A32 can dampen A25 output through the parvalbumin inhibitory microsystem in the deep layers of A25. A32 thus may flexibly recruit or reduce activity in A25 to maintain emotional equilibrium, a process that is disrupted in depression. Moreover, pyramidal neurons in A25 had a heightened density of NMDARs, which are the targets of novel rapid-acting antidepressants. Pharmacologic antagonism of NMDARs in patients with depression may reduce excitability in A25, mimicking the effects of the neurotypical serial pathway identified here.SIGNIFICANCE STATEMENT The anterior cingulate is a critical hub in prefrontal networks through connections with functionally distinct areas. Dorsolateral and polar prefrontal areas that are associated with complex cognition are connected with the anterior cingulate in a pattern that allows them to indirectly control downstream activity from the anterior cingulate to the subgenual cingulate, which is associated with heightened activity and negative affect in depression. This set of pathways provides a circuit mechanism for emotional regulation, with the anterior cingulate playing a balancing role for integration of cognitive and emotional processes. Disruption of these pathways may perturb network function and the ability to regulate cognitive and affective processes based on context.

Parallel trends in cortical gray and white matter architecture and connections in primates allow fine study of pathways in humans and reveal network disruptions in autism.

Noninvasive imaging and tractography methods have yielded information on broad communication networks but lack resolution to delineate intralaminar cortical and subcortical pathways in humans. An important unanswered question is whether we can use the wealth of precise information on pathways from monkeys to understand connections in humans. We addressed this question within a theoretical framework of systematic cortical variation and used identical high-resolution methods to compare the architecture of cortical gray matter and the white matter beneath, which gives rise to short- and long-distance pathways in humans and rhesus monkeys. We used the prefrontal cortex as a model system because of its key role in attention, emotions, and executive function, which are processes often affected in brain diseases. We found striking parallels and consistent trends in the gray and white matter architecture in humans and monkeys and between the architecture and actual connections mapped with neural tracers in rhesus monkeys and, by extension, in humans. Using the novel architectonic portrait as a base, we found significant changes in pathways between nearby prefrontal and distant areas in autism. Our findings reveal that a theoretical framework allows study of normal neural communication in humans at high resolution and specific disruptions in diverse psychiatric and neurodegenerative diseases.

Specificity of Primate Amygdalar Pathways to Hippocampus.

The amygdala projects to hippocampus in pathways through which affective or social stimuli may influence learning and memory. We investigated the still unknown amygdalar termination patterns and their postsynaptic targets in hippocampus from system to synapse in rhesus monkeys of both sexes. The amygdala robustly innervated the stratum lacunosum-moleculare layer of cornu ammonis fields and uncus anteriorly. Sparser terminations in posterior hippocampus innervated the radiatum and pyramidal layers at the prosubicular/CA1 juncture. The terminations, which were larger than other afferents in the surrounding neuropil, position the amygdala to influence hippocampal input anteriorly, and its output posteriorly. Most amygdalar boutons (76-80%) innervated spines of excitatory hippocampal neurons, and most of the remaining innervated presumed inhibitory neurons, identified by morphology and label with parvalbumin or calretinin, which distinguished nonoverlapping neurochemical classes of hippocampal inhibitory neurons. In CA1, amygdalar axons innervated some calretinin neurons, which disinhibit pyramidal neurons. By contrast, in CA3 the amygdala innervated both calretinin and parvalbumin neurons; the latter strongly inhibit nearby excitatory neurons. In CA3, amygdalar pathways also made closely spaced dual synapses on excitatory neurons. The strong excitatory synapses in CA3 may facilitate affective context representations and trigger sharp-wave ripples associated with memory consolidation. When the amygdala is excessively activated during traumatic events, the specialized innervation of excitatory neurons and the powerful parvalbumin inhibitory neurons in CA3 may allow the suppression of activity of nearby neurons that receive weaker nonamygdalar input, leading to biased passage of highly charged affective stimuli and generalized fear.SIGNIFICANCE STATEMENT Strong pathways from the amygdala targeted the anterior hippocampus, and more weakly its posterior sectors, positioned to influence a variety of emotional and cognitive functions. In hippocampal field CA1, the amygdala innervated some calretinin neurons, which disinhibit excitatory neurons. By contrast, in CA3 the amygdala innervated calretinin as well as some of the powerful parvalbumin inhibitory neurons and may help balance the activity of neural ensembles to allow social interactions, learning, and memory. These results suggest that when the amygdala is hyperactive during emotional upheaval, it strongly activates excitatory hippocampal neurons and parvalbumin inhibitory neurons in CA3, which can suppress nearby neurons that receive weaker input from other sources, biasing the passage of stimuli with high emotional import and leading to generalized fear.

Cortical Connections Position Primate Area 25 as a Keystone for Interoception, Emotion, and Memory.

The structural and functional integrity of subgenual cingulate area 25 (A25) is crucial for emotional expression and equilibrium. A25 has a key role in affective networks, and its disruption has been linked to mood disorders, but its cortical connections have yet to be systematically or fully studied. Using neural tracers in rhesus monkeys, we found that A25 was densely connected with other ventromedial and posterior orbitofrontal areas associated with emotions and homeostasis. A moderate pathway linked A25 with frontopolar area 10, an area associated with complex cognition, which may regulate emotions and dampen negative affect. Beyond the frontal lobe, A25 was connected with auditory association areas and memory-related medial temporal cortices, and with the interoceptive-related anterior insula. A25 mostly targeted the superficial cortical layers of other areas, where broadly dispersed terminations comingled with modulatory inhibitory or disinhibitory microsystems, suggesting a dominant excitatory effect. The architecture and connections suggest that A25 is the consummate feedback system in the PFC. Conversely, in the entorhinal cortex, A25 pathways terminated in the middle-deep layers amid a strong local inhibitory microenvironment, suggesting gating of hippocampal output to other cortices and memory storage. The graded cortical architecture and associated laminar patterns of connections suggest how areas, layers, and functionally distinct classes of inhibitory neurons can be recruited dynamically to meet task demands. The complement of cortical connections of A25 with areas associated with memory, emotion, and somatic homeostasis provide the circuit basis to understand its vulnerability in psychiatric and neurologic disorders.SIGNIFICANCE STATEMENT Integrity of the prefrontal subgenual cingulate cortex is crucial for healthy emotional function. Subgenual area 25 (A25) is mostly linked with other prefrontal areas associated with emotion in a dense network positioned to recruit large fields of cortex. In healthy states, A25 is associated with internal states, autonomic function, and transient negative affect. Constant hyperactivity in A25 is a biomarker for depression in humans and may trigger extensive activation in its dominant connections with areas associated with emotions and internal balance. A pathway between A25 and frontopolar area 10 may provide a critical link to regulate emotions and dampen persistent negative affect, which may be explored for therapeutic intervention in depression.

Posterior Orbitofrontal and Anterior Cingulate Pathways to the Amygdala Target Inhibitory and Excitatory Systems with Opposite Functions.

The bidirectional dialogue of the primate posterior orbitofrontal cortex (pOFC) with the amygdala is essential in cognitive-emotional functions. The pOFC also sends a uniquely one-way excitatory pathway to the amygdalar inhibitory intercalated masses (IM), which inhibit the medial part of the central amygdalar nucleus (CeM). Inhibition of IM has the opposite effect, allowing amygdalar activation of autonomic structures and emotional arousal. Using multiple labeling approaches to identify pathways and their postsynaptic sites in the amygdala in rhesus monkeys, we found that the anterior cingulate cortex innervated mostly the basolateral and CeM amygdalar nuclei, poised to activate CeM for autonomic arousal. By contrast, a pathway from pOFC to IM exceeded all other pathways to the amygdala by density and size and proportion of large and efficient terminals. Moreover, whereas pOFC terminals in IM innervated each of the three distinct classes of inhibitory neurons, most targeted neurons expressing dopamine- and cAMP-regulated phosphoprotein (DARPP-32+), known to be modulated by dopamine. The predominant pOFC innervation of DARPP-32+ neurons suggests activation of IM and inhibition of CeM, resulting in modulated autonomic function. By contrast, inhibition of DARPP-32 neurons in IM by high dopamine levels disinhibits CeM and triggers autonomic arousal. The findings provide a mechanism to help explain how a strong pOFC pathway, which is poised to moderate activity of CeM, through IM, can be undermined by the high level of dopamine during stress, resulting in collapse of potent inhibitory mechanisms in the amygdala and heightened autonomic drive, as seen in chronic anxiety disorders.SIGNIFICANCE STATEMENT The dialogue between prefrontal cortex and amygdala allows thoughts and emotions to influence actions. The posterior orbitofrontal cortex sends a powerful pathway that targets a special class of amygdalar intercalated mass (IM) inhibitory neurons, whose wiring may help modulate autonomic function. By contrast, the anterior cingulate cortex innervates other amygdalar parts, activating circuits to help avoid danger. Most IM neurons in primates label for the protein DARPP-32, known to be activated or inhibited based on the level of dopamine. Stress markedly increases dopamine release and inhibits IM neurons, compromises prefrontal control of the amygdala, and sets off a general alarm system as seen in affective disorders, such as chronic anxiety and post-traumatic stress disorder.

Pathway mechanism for excitatory and inhibitory control in working memory.

Humans engage in many daily activities that rely on working memory, the ability to hold and sequence information temporarily to accomplish a task. We focus on the process of working memory, based on circuit mechanisms for attending to relevant signals and suppressing irrelevant stimuli. We discuss that connections critically depend on the systematic variation in laminar structure across all cortical systems. Laminar structure is used to group areas into types regardless of their placement in the cortex, ranging from low-type agranular areas that lack layer IV to high-type areas that have six well-delineated layers. Connections vary in laminar distribution and strength based on the difference in type between linked areas, according to the "structural model" (Barbas H, Rempel-Clower N. Cereb Cortex 7: 635-646, 1997). The many possible pathways thus vary systematically by laminar distribution and strength, and they interface with excitatory neurons to select relevant stimuli and with functionally distinct inhibitory neurons that suppress activity at the site of termination. Using prefrontal pathways, we discuss how systematic architectonic variation gives rise to diverse pathways that can be recruited, along with amygdalar and hippocampal pathways that provide sensory, affective, and contextual information. The prefrontal cortex is also connected with thalamic nuclei that receive the output of the basal ganglia and cerebellum, which may facilitate fast sequencing of information. The complement of connections and their interface with distinct inhibitory neurons allows dynamic recruitment of areas and shifts in cortical rhythms to meet rapidly changing demands of sequential components of working memory tasks.

Opposite development of short- and long-range anterior cingulate pathways in autism.

Autism has been linked with the changes in brain connectivity that disrupt neural communication, especially involving frontal networks. Pathological changes in white matter are evident in adults with autism, particularly affecting axons below the anterior cingulate cortices (ACC). It is still unknown whether axon pathology appears early or late in development and whether it changes or not from childhood through adulthood. To address these questions, we examined typical and pathological development of about 1 million axons in post-mortem brains of children, adolescents, and adults with and without autism (ages 3-67 years). We used high-resolution microscopy to systematically sample and study quantitatively the fine structure of myelinated axons in the white matter below ACC. We provide novel evidence of changes in the density, size and trajectories of ACC axons in typical postnatal development from childhood through adulthood. Against the normal profile of axon development, our data revealed lower density of myelinated axons that connect ACC with neighboring cortices in children with autism. In the course of development the proportion of thin axons, which form short-range pathways, increased significantly in individuals with autism, but remained flat in controls. In contrast, the relative proportion of thick axons, which form long-range pathways, increased from childhood to adulthood in the control group, but decreased in autism. Our findings provide a timeline for profound changes in axon density and thickness below ACC that affect axon physiology in a direction suggesting bias in short over distant neural communication in autism. Importantly, measures of axon density, myelination, and orientation provide white matter anisotropy/diffusivity estimates at the level of single axons. The structural template established can be used to compare with measures obtained from imaging in living subjects, and guide analysis of functional and structural imaging data from humans for comparison with pathological states.

Anterior Cingulate Pathways May Affect Emotions Through Orbitofrontal Cortex.

The anterior cingulate cortex (ACC) and posterior orbitofrontal cortex (pOFC) are associated with emotional regulation. These regions are old in phylogeny and have widespread connections with eulaminate neocortices, intricately linking areas associated with emotion and cognition. The ACC and pOFC have distinct cortical and subcortical connections and are also interlinked, but the pattern of their connections-which may be used to infer the flow of information between them-is not well understood. Here we found that pathways from ACC area 32 innervated all pOFC areas with a significant proportion of large and efficient terminals, seen at the level of the system and the synapse. The pathway from area 32 targeted overwhelmingly elements of excitatory neurons in pOFC, with few postsynaptic sites found on presumed inhibitory neurons. Moreover, pathways from area 32 originated mostly in the upper layers and innervated preferentially the middle-deep layers of the least differentiated pOFC areas, in a pattern reminiscent of feedforward communication. Pathway terminations from area 32 overlapped in the deep layers of pOFC with output pathways that project to the thalamus and the amygdala, and may have cascading downstream effects on emotional and cognitive processes and their disruption in psychiatric disorders.

Mirror trends of plasticity and stability indicators in primate prefrontal cortex.

Research on plasticity markers in the cerebral cortex has largely focused on their timing of expression and role in shaping circuits during critical and normal periods. By contrast, little attention has been focused on the spatial dimension of plasticity-stability across cortical areas. The rationale for this analysis is based on the systematic variation in cortical structure that parallels functional specialization and raises the possibility of varying levels of plasticity. Here, we investigated in adult rhesus monkeys the expression of markers related to synaptic plasticity or stability in prefrontal limbic and eulaminate areas that vary in laminar structure. Our findings revealed that limbic areas are impoverished in three markers of stability: intracortical myelin, the lectin Wisteria floribunda agglutinin, which labels perineuronal nets, and parvalbumin, which is expressed in a class of strong inhibitory neurons. By contrast, prefrontal limbic areas were enriched in the enzyme calcium/calmodulin-dependent protein kinase II (CaMKII), known to enhance plasticity. Eulaminate areas have more elaborate laminar architecture than limbic areas and showed the opposite trend: they were enriched in markers of stability and had lower expression of the plasticity-related marker CaMKII. The expression of glial fibrillary acidic protein (GFAP), a marker of activated astrocytes, was also higher in limbic areas, suggesting that cellular stress correlates with the rate of circuit reshaping. Elevated markers of plasticity may endow limbic areas with flexibility necessary for learning and memory within an affective context, but may also render them vulnerable to abnormal structural changes, as seen in neurologic and psychiatric diseases.

The Emotional Gatekeeper: A Computational Model of Attentional Selection and Suppression through the Pathway from the Amygdala to the Inhibitory Thalamic Reticular Nucleus.

In a complex environment that contains both opportunities and threats, it is important for an organism to flexibly direct attention based on current events and prior plans. The amygdala, the hub of the brain's emotional system, is involved in forming and signaling affective associations between stimuli and their consequences. The inhibitory thalamic reticular nucleus (TRN) is a hub of the attentional system that gates thalamo-cortical signaling. In the primate brain, a recently discovered pathway from the amygdala sends robust projections to TRN. Here we used computational modeling to demonstrate how the amygdala-TRN pathway, embedded in a wider neural circuit, can mediate selective attention guided by emotions. Our Emotional Gatekeeper model demonstrates how this circuit enables focused top-down, and flexible bottom-up, allocation of attention. The model suggests that the amygdala-TRN projection can serve as a unique mechanism for emotion-guided selection of signals sent to cortex for further processing. This inhibitory selection mechanism can mediate a powerful affective 'framing' effect that may lead to biased decision-making in highly charged emotional situations. The model also supports the idea that the amygdala can serve as a relevance detection system. Further, the model demonstrates how abnormal top-down drive and dysregulated local inhibition in the amygdala and in the cortex can contribute to the attentional symptoms that accompany several neuropsychiatric disorders.

Pathways for Emotions: Specializations in the Amygdalar, Mediodorsal Thalamic, and Posterior Orbitofrontal Network.

The primate amygdala projects to posterior orbitofrontal cortex (pOFC) directly and possibly indirectly through a pathway to the magnocellular mediodorsal thalamic nucleus (MDmc), which may convey signals about the significance of stimuli. However, because MDmc receives input from structures in addition to the amygdala and MDmc projects to areas in addition to pOFC, it is unknown whether amygdalar pathways in MDmc innervate pOFC-bound neurons. We addressed this issue using double- or triple-labeling approaches to identify pathways and key cellular and molecular features in rhesus monkeys. We found that amygdalar terminations innervated labeled neurons in MDmc that project to pOFC. Projection neurons in MDmc directed to pOFC included comparatively fewer "core" parvalbumin neurons that project focally to the middle cortical layers and more "matrix" calbindin neurons that project expansively to the upper cortical layers. In addition, a small and hitherto unknown pathway originated from MDmc calretinin neurons and projected to pOFC. Further, whereas projection neurons directed to MDmc and to pOFC were intermingled in the amygdala, none projected to both structures. Larger amygdalar neurons projected to MDmc and expressed the vesicular glutamate transporter 2 (VGLUT2), which is found in highly efficient "driver" pathways. In contrast, smaller amygdalar neurons directed to pOFC expressed VGLUT1 found in modulatory pathways. The indirect pathway from the amygdala to pOFC via MDmc may provide information about the emotional significance of events and, along with a parallel direct pathway, ensures transfer of signals to all layers of pOFC. SIGNIFICANCE STATEMENT: The amygdala-the brain's center for emotions-is strongly linked with the orbital cortex, a region associated with social interactions. This study provides evidence that a robust pathway from the amygdala reaches neurons in the thalamus that link directly with the orbital cortex, forming a tight tripartite network. The dual pathways from the amygdala to the orbital cortex and to the thalamus are distinct by morphology, neurochemistry, and function. This tightly linked network suggests the presence of fool-proof avenues for emotions to influence high-order cortical areas associated with affective reasoning. Specific nodes of this tripartite network are disrupted in psychiatric diseases, divorcing areas that integrate emotions and thoughts for decisions and flexible behavior.

The primate connectome in context: Principles of connections of the cortical visual system.

Which principles determine the organization of the intricate network formed by nerve fibers that link the primate cerebral cortex? We addressed this issue for the connections of primate visual cortices by systematically analyzing how the existence or absence of connections, their density as well as laminar patterns of projection origins and terminations are correlated with distance, similarity in cortical type as well as neuronal density or the thickness of cortical areas. Analyses were based on four extensive compilations of qualitative as well as quantitative data for connections of the primate visual cortical system in macaque monkeys (Felleman and Van Essen 1991; Barbas 1986; Barbas and Rempel-Clower 1997; Barone et al. 2000; Markov et al. 2014). Distance and thickness similarity were not consistently correlated with connection features, but similarity of cortical type, determined by qualitative features of laminar differentiation, or measured quantitatively as the areas' overall neuronal density, was a reliable predictor for the existence of connections between areas. Cortical type similarity was also consistently and closely correlated with characteristic laminar connection profiles: structurally dissimilar areas had origin and termination patterns that were biased to the upper or deep cortical layers, while similar areas showed more bilaminar origins and terminations. These results suggest that patterns of corticocortical connections of primate visual cortices are closely linked to the stratified architecture of the cerebral cortex. In particular, the regularity of laminar projection origins and terminations arises from the structural differences between cortical areas. The observed integration of projections with the intrinsic cortical architecture provides a structural basis for advanced theories of cortical organization and function.

Prefrontal-hippocampal pathways underlying inhibitory control over memory.

A key function of the prefrontal cortex is to support inhibitory control over behavior. It is widely believed that this function extends to stopping cognitive processes as well. Consistent with this, mounting evidence establishes the role of the right lateral prefrontal cortex in a clear case of cognitive control: retrieval suppression. Retrieval suppression refers to the ability to intentionally stop the retrieval process that arises when a reminder to a memory appears. Functional imaging data indicate that retrieval suppression involves top-down modulation of hippocampal activity by the dorsolateral prefrontal cortex, but the anatomical pathways supporting this inhibitory modulation remain unclear. Here we bridge this gap by integrating key findings about retrieval suppression observed through functional imaging with a detailed consideration of relevant anatomical pathways observed in non-human primates. Focusing selectively on the potential role of the anterior cingulate cortex, we develop two hypotheses about the pathways mediating interactions between lateral prefrontal cortex and the medial temporal lobes during suppression, and their cellular targets: the entorhinal gating hypothesis, and thalamo-hippocampal modulation via the nucleus reuniens. We hypothesize that whereas entorhinal gating is well situated to stop retrieval proactively, thalamo-hippocampal modulation may interrupt an ongoing act of retrieval reactively. Isolating the pathways that underlie retrieval suppression holds the potential to advance our understanding of a range of psychiatric disorders characterized by persistent intrusive thoughts. More broadly, an anatomical account of retrieval suppression would provide a key model system for understanding inhibitory control over cognition.