Intracerebral injection of brain extracts containing amyloid or tau aggregates in transgenic animals can induce cerebral amyloidosis and tau pathology. We extracted pure populations of tau oligomers directly from the cerebral cortex of Alzheimer disease (AD) brain. These oligomers are potent inhibitors of long term potentiation (LTP) in hippocampal brain slices and disrupt memory in wild type mice. We observed for the first time that these authentic brain-derived tau oligomers propagate abnormal tau conformation of endogenous murine tau after prolonged incubation. The conformation and hydrophobicity of tau oligomers play a critical role in the initiation and spread of tau pathology in the naïve host in a manner reminiscent of sporadic AD.

Cognitive deficits such as impaired decision-making can be a consequence of persistent pain. Normal functions of the intact amygdala and prefrontal cortex are required for emotion-based decision-making that relies on the ability to assess risk, attribute value, and identify advantageous strategies. We tested the hypothesis that pain-related cognitive deficits result from amygdala-driven impairment of medial prefrontal cortical (mPFC) function. To do this, we used electrophysiological single-unit recordings in vivo, patch clamp in brain slices, and various behavioral assays to show that increased neuronal activity in the amygdala in an animal model of arthritis pain was accompanied by decreased mPFC activation and impaired decision-making. Furthermore, pharmacologic inhibition (with a corticotropin-releasing factor 1 receptor antagonist) of pain-related hyperactivity in the basolateral amygdala (BLA), but not central amygdala (CeA), reversed deactivation of mPFC pyramidal cells and improved decision-making deficits. Pain-related cortical deactivation resulted from a shift of balance between inhibitory and excitatory synaptic transmission. Direct excitatory transmission to mPFC pyramidal cells did not change in the pain model, whereas polysynaptic inhibitory transmission increased. GABAergic transmission was reduced by non-NMDA receptor antagonists, suggesting that synaptic inhibition was glutamate driven. The results are consistent with a model of BLA-driven feedforward inhibition of mPFC neurons. In contrast to the differential effects of BLA versus CeA hyperactivity on cortical-cognitive functions, both amygdala nuclei modulate emotional-affective pain behavior. Thus, this study shows that the amygdala contributes not only to emotional-affective but also cognitive effects of pain. The novel amygdalo-cortical pain mechanism has important implications for our understanding of amygdala functions and amygdalo-cortical interactions.

A limbic brain area the amygdala plays a key role in emotional responses and affective states and disorders such as learned fear, anxiety and depression. The amygdala has also emerged as an important brain center for the emotional-affective dimension of pain and for pain modulation. Hyperactivity in the laterocapsular division of the central nucleus of the amygdala (CeLC, also termed the “nociceptive amygdala”) accounts for pain-related emotional responses and anxiety-like behavior. Abnormally enhanced output from the CeLC is the consequence of an imbalance between excitatory and inhibitory mechanisms. Impaired inhibitory control mediated by a cluster of GABAergic interneurons in the intercalated cell masses (ITC) allows the development of glutamate- and neuropeptide-driven synaptic plasticity of excitatory inputs from the brainstem (parabrachial area) and from the lateral-basolateral amygdala network (LA-BLA, site of integration of polymodal sensory information). BLA hyperactivity also generates abnormally enhanced feedforward inhibition of principal cells in the medial prefrontal cortex (mPFC), a limbic cortical area that is strongly interconnected with the amygdala. Pain-related mPFC deactivation results in cognitive deficits and failure to engage cortically driven ITC-mediated inhibitory control of amygdala processing. Impaired cortical control allows the uncontrolled persistence of amygdala pain mechanisms.

Emotional-affective and cognitive dimensions of pain are less well understood than nociceptive and nocifensive components, but the forebrain is believed to play an important role. Recent evidence suggests subcortical and cortical brain areas outside the traditional pain processing network contribute critically to emotional-affective responses and cognitive deficits related to pain. These brain areas include different nuclei of the amygdala and certain prefrontal cortical areas. Their roles in various aspects of pain will be discussed. Biomarkers of cortical dysfunction are being identified that may evolve into therapeutic targets to modulate pain experience and improve pain-related cognitive impairment. Supporting data from preclinical studies in neuropathic pain models will be presented. Neuroimaging analysis provides evidence for plastic changes in the pain processing brain network. Results of clinical studies in neuropathic pain patients suggest that neuroimaging may help determine mechanisms of altered brain functions in pain as well as monitor the effects of pharmacologic interventions to optimize treatment in individual patients. Recent progress in the analysis of higher brain functions emphasizes the concept of pain as a multidimensional experience and the need for integrative approaches to determine the full spectrum of harmful or protective neurobiological changes in pain.

Pain has a strong emotional-affective dimension, and the amygdala plays a key role in emotionality. Mechanisms of pain-related changes in the amygdala were studied at the cellular and molecular levels in a model of arthritis pain. The influence of the arthritic condition induced in vivo on synaptic transmission and group I metabotropic glutamate receptor (mGluR1 and mGluR5) function was examined in vitro using whole-cell voltage-clamp recordings of neurons in the central nucleus of the amygdala (CeA). G-protein-coupled mGluRs are implicated in various forms of neuroplasticity as well as in neurological and psychiatric disorders. Synaptic transmission was evoked by electrical stimulation of afferents from the basolateral amygdala (BLA) and the pontine parabrachial (PB) area in brain slices from control (untreated or saline-injected) rats and from arthritic rats. This study shows enhanced synaptic transmission of nociceptivespecific inputs (PB3 CeA synapse) and polymodal sensory inputs (BLA3 CeA synapse) in the arthritis model. CeA neurons from arthritic rats also developed increased excitability compared with control CeA neurons. Synaptic plasticity in the CeA was accompanied by increased presynaptic mGluR1 function and upregulation of mGluR1 and mGluR5. A selective mGluR1 antagonist reduced transmission in CeA neurons from arthritic animals but not in control neurons, and increased levels of mGluR1 and mGluR5 protein were measured in the CeA of arthritic rats compared with controls. Our results show that plastic changes in the amygdala in an arthritis model that produces prolonged pain involve a critical switch of presynaptic mGluR1 expression and function.

The role of neuropeptides in synaptic plasticity is less well understood than that of classical transmitters such as glutamate. Here we report the importance of the G-protein-coupled calcitonin gene-related peptide (CGRP1) receptor as a critical link between amygdala plasticity and pain behavior. A key player in emotionality and affective disorders, the amygdala has been implicated in the well documented, but mechanistically unexplained, relationship between pain and affect. Our electrophysiological and pharmacological in vitro (patch-clamp recordings) and in vivo (extracellular single-unit recordings) data show that selective CGRP1 receptor antagonists (CGRP 8 -37 and BIBN4096BS) in the amygdala reverse arthritis pain-related plasticity through a protein kinase A (PKA)-dependent postsynaptic mechanism that involves NMDA receptors. CGRP1 receptor antagonists inhibited synaptic plasticity in the laterocapsular division of the central nucleus of the amygdala (CeLC) in brain slices from arthritic rats compared with normal controls. The effects were accompanied by decreased neuronal excitability and reduced amplitude, but not frequency, of miniature EPSCs; paired-pulse facilitation was unaffected. The antagonist effects were occluded by a PKA inhibitor. CGRP1 receptor blockade also directly inhibited NMDA-evoked, but not AMPA-evoked, membrane currents. Together, these data suggest a postsynaptic site of action. At the systems level, the antagonists reversed the sensitization of nociceptive CeLC neurons in anesthetized rats in the arthritis pain model. Importantly, CGRP1 receptor blockade in the CeLC inhibited spinal (hindlimb withdrawal reflexes) and supraspinal pain behavior of awake arthritic rats, including affective responses such as ultrasonic vocalizations. This study provides direct evidence for the critical dependence of pain behavior on CGRP1-mediated amygdala plasticity.

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The amygdala is a limbic brain region that plays a key role in emotional processing, neuropsychiatric disorders, and the emotional-affective dimension of pain. Preclinical and clinical studies have identified amygdala hyperactivity as well as impairment of cortical control mechanisms in pain states. Hyperactivity of basolateral amygdala (BLA) neurons generates enhanced feedforward inhibition and deactivation of the medial prefrontal cortex (mPFC), resulting in pain-related cognitive deficits. The mPFC sends excitatory projections to GABAergic neurons in the intercalated cell mass (ITC) in the amygdala, which project to the laterocapsular division of the central nucleus of the amygdala (CeLC; output nucleus) and serve gating functions for amygdala output. Impairment of these cortical control mechanisms allows the development of amygdala pain plasticity. Mechanisms of abnormal amygdala activity in pain with particular focus on loss of cortical control mechanisms as well as new strategies to correct pain-related amygdala dysfunction will be discussed in the present review.