Functional neuroanatomy of basal forebrain projections to the basolateral amygdala: Transmitters, receptors, and neuronal subpopulations.

The projections of the basal forebrain (BF) to the hippocampus and neocortex have been extensively studied and shown to be important for higher cognitive functions, including attention, learning, and memory. Much less is known about the BF projections to the basolateral nuclear complex of the amygdala (BNC), although the cholinergic innervation of this region by the BF is actually far more robust than that of cortical areas. This review will focus on light and electron microscopic tract-tracing and immunohistochemical (IHC) studies, many of which were published in the last decade, that have analyzed the relationship of BF inputs and their receptors to specific neuronal subtypes in the BNC in order to better understand the anatomical substrates of BF-BNC circuitry.

Acetylcholine Engages Distinct Amygdala Microcircuits to Gate Internal Theta Rhythm.

Acetylcholine (ACh) is released from basal forebrain cholinergic neurons in response to salient stimuli and engages brain states supporting attention and memory. These high ACh states are associated with theta oscillations, which synchronize neuronal ensembles. Theta oscillations in the basolateral amygdala (BLA) in both humans and rodents have been shown to underlie emotional memory, yet their mechanism remains unclear.

Functional neuroanatomy of monoaminergic systems in the basolateral nuclear complex of the amygdala: Neuronal targets, receptors, and circuits.

This review discusses neuroanatomical aspects of the three main monoaminergic systems innervating the basolateral nuclear complex (BNC) of the amygdala (serotonergic, noradrenergic, and dopaminergic systems). It mainly focuses on immunohistochemical (IHC) and in situ hybridization (ISH) studies that have analyzed the relationship of specific monoaminergic inputs and their receptors to specific neuronal subtypes in the BNC in order to better understand the anatomical substrates of the monoaminergic modulation of BNC circuitry. First, light and electron microscopic IHC investigations identifying the main BNC neuronal subpopulations and characterizing their local circuitry, including connections with discrete PN compartments and other INs, are reviewed.

Differential Regulation of Prelimbic and Thalamic Transmission to the Basolateral Amygdala by Acetylcholine Receptors.

The amygdalar anterior basolateral nucleus (BLa) plays a vital role in emotional behaviors. This region receives dense cholinergic projections from basal forebrain which are critical in regulating neuronal activity in BLa. Cholinergic signaling in BLa has also been shown to modulate afferent glutamatergic inputs to this region.

Colocalization of M1 muscarinic cholinergic receptors and NMDA receptors in dendrites and spines of pyramidal neurons of the mouse basolateral amygdala: An ultrastructural analysis.

The cholinergic innervation of the neocortex, hippocampus, and basolateral amygdala is critical for higher cognitive functions, including attention and memory. One action of ACh in the hippocampus is the potentiation of NMDA receptor (NMDAR) currents in pyramidal neurons (PNs) by M1 muscarinic receptors (M1Rs). The increase in these currents enhances long-term potentiation (LTP), an important mechanism for memory formation.

Specific neuronal subpopulations in the amygdala of macaque monkeys express high levels of nonphosphorylated neurofilaments.

Pyramidal neurons in the neocortex that express nonphosphorylated neurofilaments (NPNFs) are especially vulnerable to degeneration in Alzheimer's disease. Since the basolateral nuclear complex of the amygdala (BNC) and cortical nuclear complex of the amygdala (CNC) are cortex-like structures, containing both pyramidal (PNs) and nonpyramidal neurons (NPNs), it is of interest to determine which cell types in the primate BNC and CNC are NPNF+. We also studied NPNF expression in the non-cortex-like nuclei of the amygdala (central and medial nuclei).

Specific neuronal subpopulations in the rat basolateral amygdala express high levels of nonphosphorylated neurofilaments.

Cortical pyramidal neurons (PNs) containing nonphosphorylated neurofilaments (NNFs) localized with the SMI-32 monoclonal antibody have been shown to be especially vulnerable to degeneration in Alzheimer's disease (AD). The present investigation is the first to study the expression of SMI-32+ NNFs in neurons of the basolateral nuclear complex of the amygdala (BNC), which contains cortex-like PNs and nonpyramidal neurons (NPNs). We observed that PNs in the rat basolateral nucleus (BL), but not in the lateral (LAT) or basomedial (BM) nuclei, have significant levels of SMI-32-ir in their somata with antibody diluents that did not contain Triton X-100, but staining in these cells was greatly attenuated when the antibody diluent contained 0.

Neuronal localization of m1 muscarinic receptor immunoreactivity in the monkey basolateral amygdala.

The basolateral nuclear complex (BNC) of the amygdala plays an important role in the generation of emotional/motivational behavior and the consolidation of emotional memories. Activation of M1 cholinergic receptors (M1Rs) in the BNC is critical for memory consolidation. Previous receptor binding studies in the monkey amygdala demonstrated that the BNC has a high density of M1Rs, but did not have sufficient resolution to identify which neurons in the BNC expressed them.

Immunohistochemical Identification of Interneuronal Subpopulations in the Basolateral Amygdala of the Rhesus Monkey (Macaca mulatta).

Inhibitory circuits in the basolateral nuclear complex of the amygdala (BNC) critical for controlling the acquisition, expression, and extinction of emotional responses are mediated by GABAergic interneurons (INs). Studies in rodents have demonstrated that separate IN subpopulations, identified by their expression of calcium-binding proteins and neuropeptides, play discrete roles in the intrinsic circuitry of the BNC. Far less is known about IN subpopulations in primates.

Expression of the type 1 cannabinoid receptor (CB1R) in CCK-immunoreactive axon terminals in the basolateral amygdala of the rhesus monkey (Macaca mulatta).

Studies in rodents have shown that interactions between cholecystokinin (CCK) and the endogenous cannabinoid system in the basolateral nuclear complex of the amygdala (BNC) modulate anxiety-like behavior and fear learning/expression. One of the main cell types implicated is a CCK-immunoreactive (CCK+) basket cell that innervates the somata of pyramidal projection neurons (PNs) and expresses the type 1 cannabinoid receptor (CB1R) in its axon terminals. Although numerous studies have elucidated the anatomy and physiology of these CCK+/CB1R + interneurons in rodents, it has not been determined if they exist in primates.

Nonpyramidal neurons in the primate basolateral amygdala: A Golgi study in the baboon (Papio cynocephalus) and long-tailed macaque (Macaca fascicularis).

Nonpyramidal GABAergic interneurons in the basolateral nuclear complex (BNC) of the amygdala are critical for the regulation of emotion. Remarkably, there have been no Golgi studies of these neurons in nonhuman primates. Therefore, in the present study we investigated the morphology of nonpyramidal neurons (NPNs) in the BNC of the baboon and monkey using the Golgi technique.

Diverse glutamatergic inputs target spines expressing M1 muscarinic receptors in the basolateral amygdala: An ultrastructural analysis.

Although it is known that acetylcholine acting through M1 muscarinic receptors (M1Rs) is essential for memory consolidation in the anterior basolateral nucleus of the amygdala (BLa), virtually nothing is known about the circuits involved. In the hippocampus M1R activation facilitates long-term potentiation (LTP) by potentiating NMDA glutamate receptor (NMDAR) currents. The majority of NMDAR+ profiles in the BLa are spines.

Cholecystokinin immunoreactive neurons in the basolateral amygdala of the rhesus monkey (Macaca mulatta).

Several distinct subpopulations of interneurons (INs) in the amygdalar basolateral nuclear complex (BNC) of the rat can be recognized on the basis of their expression of calcium-binding proteins and neuropeptides, including parvalbumin (PV), somatostatin (SOM), calretinin (CR), and cholecystokinin (CCK). In the rat BNC CCK is expressed in two separate IN subpopulations, termed large (CCK ) and small (CCK ). These subpopulations exhibit distinct connections indicative of discrete functional roles in the circuitry of the BNC.

Perineuronal nets labeled by monoclonal antibody VC1.1 ensheath interneurons expressing parvalbumin and calbindin in the rat amygdala.

Perineuronal nets (PNNs) are specialized condensations of extracellular matrix that ensheath particular neuronal subpopulations in the brain and spinal cord. PNNs regulate synaptic plasticity, including the encoding of fear memories by the amygdala. The present immunohistochemical investigation studied PNN structure and distribution, as well as the neurochemistry of their ensheathed neurons, in the rat amygdala using monoclonal antibody VC1.

Evidence for M muscarinic receptor modulation of axon terminals and dendrites in the rodent basolateral amygdala: An ultrastructural and electrophysiological analysis.

The basolateral amygdala receives a very dense cholinergic innervation from the basal forebrain that is important for memory consolidation. Although behavioral studies have shown that both M and M muscarinic receptors are critical for these mnemonic functions, there have been very few neuroanatomical and electrophysiological investigations of the localization and function of different types of muscarinic receptors in the amygdala. In the present study we investigated the subcellular localization of M muscarinic receptors (MRs) in the anterior basolateral nucleus (BLa) of the mouse, including the localization of MRs in parvalbumin (PV) immunoreactive interneurons, using double-labeling immunoelectron microscopy.

Functional neuroanatomy of amygdalohippocampal interconnections and their role in learning and memory.

The amygdalar nuclear complex and hippocampal/parahippocampal region are key components of the limbic system that play a critical role in emotional learning and memory. This Review discusses what is currently known about the neuroanatomy and neurotransmitters involved in amygdalo-hippocampal interconnections, their functional roles in learning and memory, and their involvement in mnemonic dysfunctions associated with neuropsychiatric and neurological diseases. Tract tracing studies have shown that the interconnections between discrete amygdalar nuclei and distinct layers of individual hippocampal/parahippocampal regions are robust and complex.

Light and electron microscopic analysis of enkephalin-like immunoreactivity in the basolateral amygdala, including evidence for convergence of enkephalin-containing axon terminals and norepinephrine transporter-containing axon terminals onto common targets.

Modulatory interactions of opioids and norepinephrine (NE) in the anterior subdivision of the basolateral nucleus of the amygdala (BLa) are critical for the consolidation of memories of emotionally arousing experiences. Although there have been several studies of the noradrenergic system in the amygdalar basolateral nuclear complex (BLC), little is known about the chemical neuroanatomy of opioid systems in this region. To address this knowledge gap the present study first examined the distribution of met-enkephalin-like immunoreactivity (ENK-ir) in the BLC at the light microscopic level, and then utilized dual-labeling immunocytochemistry combined with electron microscopy to investigate the extent of convergence of NE and ENK terminals onto common structures in the BLa.

Localization of the M2 muscarinic cholinergic receptor in dendrites, cholinergic terminals, and noncholinergic terminals in the rat basolateral amygdala: An ultrastructural analysis.

Activation of M2 muscarinic receptors (M2Rs) in the rat anterior basolateral nucleus (BLa) is critical for the consolidation of memories of emotionally arousing events. The present investigation used immunocytochemistry at the electron microscopic level to determine which structures in the BLa express M2Rs. In addition, dual localization of M2R and the vesicular acetylcholine transporter protein (VAChT), a marker for cholinergic axons, was performed to determine whether M2R is an autoreceptor in cholinergic axons innervating the BLa.

Molecular Signaling Mechanisms of Natural and Synthetic Retinoids for Inhibition of Pathogenesis in Alzheimer's Disease.

Retinoids, which are vitamin A derivatives, interact through retinoic acid receptors (RARs) and retinoid X receptors (RXRs) and have profound effects on several physiological and pathological processes in the brain. The presence of retinoic acid signaling is extensively detected in the adult central nervous system, including the amygdala, cortex, hypothalamus, hippocampus, and other brain areas. Retinoids are primarily involved in neural patterning, differentiation, and axon outgrowth.

Muscarinic cholinergic receptor M1 in the rat basolateral amygdala: ultrastructural localization and synaptic relationships to cholinergic axons.

Muscarinic neurotransmission in the anterior basolateral amygdalar nucleus (BLa) mediated by the M1 receptor (M1R) is critical for memory consolidation. Although knowledge of the subcellular localization of M1R in the BLa would contribute to an understanding of cholinergic mechanisms involved in mnemonic function, there have been no ultrastructural studies of this receptor in the BLa. In the present investigation, immunocytochemistry at the electron microscopic level was used to determine which structures in the BLa express M1R.

Subpopulations of somatostatin-immunoreactive non-pyramidal neurons in the amygdala and adjacent external capsule project to the basal forebrain: evidence for the existence of GABAergic projection neurons in the cortical nuclei and basolateral nuclear complex.

The hippocampus and amygdala are key structures of the limbic system whose connections include reciprocal interactions with the basal forebrain (BF). The hippocampus receives both cholinergic and GABAergic afferents from the medial septal area of the BF. Hippocampal projections back to the medial septal area arise from non-pyramidal GABAergic neurons that express somatostatin (SOM), calbindin (CB), and neuropeptide Y (NPY).

Neuroanatomical evidence for reciprocal regulation of the corticotrophin-releasing factor and oxytocin systems in the hypothalamus and the bed nucleus of the stria terminalis of the rat: Implications for balancing stress and affect.

Activation of corticotrophin releasing factor (CRF) neurons in the paraventricular nucleus of the hypothalamus (PVN) is necessary for establishing the classic endocrine response to stress, while activation of forebrain CRF neurons mediates affective components of the stress response. Previous studies have reported that mRNA for CRF2 receptor (CRFR2) is expressed in the bed nucleus of the stria terminalis (BNST) as well as hypothalamic nuclei, but little is known about the localization and cellular distribution of CRFR2 in these regions. Using immunofluorescence with confocal microscopy, as well as electron microscopy, we demonstrate that in the BNST CRFR2-immunoreactive fibers represent moderate to strong labeling on axons terminals.

Cholinergic innervation of pyramidal cells and parvalbumin-immunoreactive interneurons in the rat basolateral amygdala.

The basolateral nucleus of the amygdala receives an extremely dense cholinergic innervation from the basal forebrain that is critical for memory consolidation. Although previous electron microscopic studies determined some of the postsynaptic targets of cholinergic afferents, the majority of postsynaptic structures were dendritic shafts whose neurons of origin were not identified. To make this determination, the present study analyzed the cholinergic innervation of the anterior subdivision of the basolateral amygdalar nucleus (BLa) of the rat using electron microscopic dual-labeling immunocytochemistry.