Miles Herkenham

• Ph.D.
• Senior Investigator at National Institute of Mental Health, National Institutes of Health

Cannabinoid receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Cannabinoid Receptors [127]) are activated by endogenous ligands that include N-arachidonoylethanolamine (anandamide), N-homo-γ-linolenoylethanolamine, N-docosatetra-7,10,13,16-enoylethanolamine and 2-arachidonoylglycerol. Potency determinations of endogenous agonists at...

Animal models of stress and stress-related disorders are also associated with blood neutrophilia. The mechanistic relevance of this to symptoms or behavior is unclear. We used cytometry, immunohistochemistry, whole tissue clearing, and single-cell sequencing to characterize the meningeal immune response to chronic social defeat (CSD) stress in mice...

Brain vascular integrity is critical for brain health, and its disruption is implicated in many brain pathologies, including psychiatric disorders. Brain-vascular barriers are a complex cellular landscape composed of endothelial, glial, mural, and immune cells. Yet currently, little is known about these brain vascular-associated cells (BVACs) in he...

Cannabinoid receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Cannabinoid Receptors [119]) are activated by endogenous ligands that include N-arachidonoylethanolamine (anandamide), N-homo-γ-linolenoylethanolamine, N-docosatetra-7,10,13,16-enoylethanolamine and 2-arachidonoylglycerol. Potency determinations of endogenous agonists at...

Immune surveillance of the brain plays an important role in health and disease. Peripheral leukocytes patrol blood-brain barrier interfaces, and after injury, monocytes cross the cerebrovasculature and follow a pattern of pro- and anti-inflammatory activity leading to tissue repair. We have shown that chronic social defeat (CSD) causes scattered va...

There is increasing interest in how immune cells, including those within the meninges at the blood-brain interface, influence brain function and mood disorders, but little data on humoral immunity in this context. Here, we show that in mice exposed to psychosocial stress, there is increased splenic B cell activation and secretion of the immunoregul...

Psychological stress and affective disorders are clinically associated with hypertension and vascular disease, but the biological links between the conditions have not been fully explored. To examine this relationship, we used chronic social defeat (CSD) stress, which produces anxiety-like and depressive-like behavioral declines in susceptible mice...

Cannabinoid receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Cannabinoid Receptors [107]) are activated by endogenous ligands that include N-arachidonoylethanolamine (anandamide), N-homo-γ-linolenoylethanolamine, N-docosatetra-7,10,13,16-enoylethanolamine and 2-arachidonoylglycerol. Potency determinations of endogenous agonists at...

Chronic social defeat (CSD) in male mice can produce anxiety and aberrant socialization. Animals susceptible to CSD show activation of microglia, which have elevated levels of oxidative stress markers. We hypothesized that microglia and reactive oxygen species (ROS) production contribute to the CSD stress-induced changes in affective behavior. Firs...

An animal’s ability to cope with or succumb to deleterious effects of chronic psychological stress may be rooted in the brain’s immune responses manifested in microglial activity. Mice subjected to chronic social defeat (CSD) were categorized as susceptible (CSD-S) or resilient (CSD-R) based on behavioral phenotyping, and their microglia were isola...

The medial prefrontal cortex (mPFC) plays a key role in top-down control of the brain’s stress axis, and its structure and function are particularly vulnerable to stress effects, which can lead to depression in humans and depressive-like states in animals. We tested whether chronic social defeat produces structural alterations in the mPFC in mice....

Clinical and basic studies of functional interactions between adaptive immunity, affective states, and brain function are reviewed, and the neural, humoral, and cellular routes of bidirectional communication between the brain and the adaptive immune system are evaluated.In clinical studies of depressed populations, lymphocytes-the principal cells o...

Background We are interested in the causal interactions between psychological stress and activity within different compartments of the immune system. Psychosocial stress has been reported to not only alter microglia morphology but also produce anxiety-like and depressive-like effects by triggering CNS infiltration of macrophages from the periphery....

Our group has recently provided novel insights into a poorly understood component of intercommunication between the brain and the immune system by showing that psychological stress can modify lymphocytes in a manner that may boost resilience to psychological stress. To demonstrate the influence of the adaptive immune system on mood states, we previ...

We examined whether cells of the adaptive immune system retain the memory of psychosocial stress and thereby alter mood states and CNS function in the host. Lymphocytes from mice undergoing chronic social defeat stress or from unstressed control mice were isolated and adoptively transferred into naive lymphopenic Rag2(-/-) mice. Changes in affectiv...

Neuropsychopharmacology, the official publication of the American College of Neuropsychopharmacology, publishing the highest quality original research and advancing our understanding of the brain and behavior.

NF-κB is a ubiquitous transcription factor that regulates immune and cell-survival signaling pathways. NF-κB has been reported to be present in neurons wherein it reportedly responds to immune and toxic stimuli, glutamate, and synaptic activity. However, because the brain contains many cell types, assays specifically measuring neuronal NF-κB activi...

Decreased interest in pleasurable stimuli including social withdrawal and reduced libido are some of the key symptomatic criteria for major depression, and thus assays that measure social and sexual behavior in rodents may be highly appropriate for modeling depressive states. Here we present a novel approach for validating rodent models of depressi...

Both social defeat stress and environmental enrichment stimulate adrenal glucocorticoid secretion, but they have opposing effects on hippocampal neurogenesis and mood. Hypothalamic-pituitary-adrenal axis dysregulation and decreased neurogenesis are consequences of social defeat. These outcomes are correlated with depressive states, but a causal rol...

Maternal immune activation (MIA) is a risk factor for the development of schizophrenia and autism. Infections during pregnancy activate the mother's immune system and alter the fetal environment, with consequential effects on CNS function and behavior in the offspring, but the cellular and molecular links between infection-induced altered fetal dev...

The characterization and cellular localization of transcription factors like NF-κB requires the use of antibodies for western blots and immunohistochemistry. However, if target protein levels are low and the antibodies not well characterized, false positive data can result. In studies of NF-κB activity in the CNS, antibodies detecting NF-κB protein...

Enriched environmental (EE) housing dampens stress-induced alterations in neurobiological systems, promotes adaptability, and extinguishes submissive behavioral traits developed during social defeat stress (SD). In the present study, we hypothesized that enrichment before SD can confer stress resiliency and, furthermore, that neuronal activity in t...

The role of altered activity of nuclear factor kappaB (NF-kappaB) in specific aspects of motivated behavior and learning and memory was examined in mice lacking the p50 subunit of the NF-kappaB/rel transcription factor family. Nfkb1-deficient mice are unable to produce p50 and show specific susceptibilities to infections and inflammatory challenges...

The subgranular zone of the adult hippocampal dentate gyrus contains a pool of neural stem cells that continuously divide and differentiate into functional granule cells. It has been shown that production of new hippocampal neurons is necessary for amelioration of stress-induced behavioral changes by antidepressants in animal models of depression....

Chronic inflammation activates the tryptophan-degrading enzyme IDO, which is well known to impair T cell proliferation. We have previously established that bacille Calmette-Guérin (BCG), an attenuated form of Mycobacterium bovis, is associated with persistent activation of IDO in the brain and chronic depressive-like behavior, but a causative role...

The type 1 interleukin-1 receptor (IL-1R1) mediates diverse functions of interleukin-1 (IL-1) in the nervous, immune, and neuroendocrine systems. It has been suggested previously that the versatile functions of IL-1 may in part be conferred by the multiple promoters of IL-1R1 that have been identified for the human IL-1R1 gene. Promoters for murine...

The transcription-intermediary-factor-2 (TIF-2) is a coactivator of the glucocorticoid receptor (GR), and its disruption would be expected to influence glucocorticoid-mediated control of the hypothalamo-pituitary-adrenal (HPA) axis. Here, we show that its targeted deletion in mice is associated with altered expression of several glucocorticoid-depe...

Lipopolysaccharide (LPS), a well-known bacterial pyrogen, is recognized by several receptors, including the Toll-like receptor 4 (TLR4), on various cells. Which of these receptors and cells are linked to fever production is unknown. By constructing 4 mouse chimeras and studying their thermoregulatory responses, we found that all 3 phases of the typ...

LPS preparations cause a variety of body temperature (T(b)) responses: monophasic fever, different phases of polyphasic fever, and hypothermia. Conventional (c) LPS preparations contain highly active lipoprotein contaminants (endotoxin proteins). Whereas LPS signals predominantly via the Toll-like receptor (TLR) 4, endotoxin proteins signal via TLR...

A property common to the immune system and the nervous system is regulation by a highly complex and adaptable network of cellular interactions. Major histocompatibility complex (MHC) class I molecules, which are ligands of antigen-specific receptors on CD8 T cells and of inhibitory receptors on natural killer cells, have an important and surprising...

Inflammatory agonists such as lipopolysaccharide (LPS) induce robust systemic as well as CNS responses after peripheral administration. Responses in the innate immune system require triggering of toll-like receptor 4 (TLR4), but the origin of CNS sequelas has been controversial. We demonstrate expression of TLR4 transcripts in mouse brain in the me...

The ubiquitous transcription factor nuclear factor (NF)-kappaB plays a prominent role in regulation of inflammatory immune responses and in cell survival. Recently, it has been found to be active in neurons, and mice lacking NF-kappaB subunits p50 or p65 show deficits in specific cognitive tasks. Here we demonstrate a strikingly low level of anxiet...

The progressive development of seizures in rats by amygdala kindling, which models temporal lobe epilepsy, allows the study of molecular regulators of enduring synaptic changes. Neurotrophins play important roles in synaptic plasticity and neuroprotection. Activin, a member of the transforming growth factor-beta superfamily of growth and differenti...

We previously showed that a methanolic extract of St John's wort (SJW) (Hypericum) and hypericin, one of its active constituents, both have delayed regulation of genes that are involved in the control of the hypothalamic-pituitary-adrenal (HPA) axis. Hyperforin, another constituent of SJW, is active in vitro and has been proposed to be the active c...

Patients with Gaucher disease have been classified as type 1 nonneuronopathic, type 2 acute neuronopathic, and type 3 chronic neuronopathic phenotypes. Increased quantities of glucocerebroside and glucosylsphingosine (glucopsychosine) are present in the brain of type 2 and type 3 Gaucher patients. Galactosylsphingosine has previously been shown to...

Studies have demonstrated neuronal expression of class I major histocompatibility complex (MHC) mRNA and protein in normal and developing brain and in response to injury or viral infection. We report neuronal expression of class I MHC mRNA in hypothalamic paraventricular nucleus (PVN) neurons in rats following systemic infection with Trypanosoma br...

Neuronal elements are increasingly suggested as primary targets of an autoimmune attack in certain neurological and neuropsychiatric diseases. Type 1 cannabinoid receptors (CB1) were selected as autoimmune targets because they are predominantly expressed on neuronal surfaces in brain and display strikingly high protein levels in striatum, hippocamp...

Two types of cannabinoid receptor have been discovered so far, CB(1) (2.1: CBD:1:CB1:), cloned in 1990, and CB(2) (2.1:CBD:2:CB2:), cloned in 1993. Distinction between these receptors is based on differences in their predicted amino acid sequence, signaling mechanisms, tissue distribution, and sensitivity to certain potent agonists and antagonists...

Interleukin-1β (IL-1β) is a pro-inflammatory cytokine that appears in brain and cerebrospinal fluid following peripheral immune challenges and central infections or injury. We examined the consequences of i.c.v. infusion of IL-1β on mRNA expression of several immune markers and on recruitment of peripheral leukocytes. Awake rats were infused with I...

Cytokines have been a multi-disciplinary research focus for over 2 decades. To date, there have been more than 15,000 articles published concerning the relationship between cytokines and the central nervous system (CNS). Over half of these articles have been published in the last 5 years. From such vast number of studies, two major topics emerge as...

Clinical studies demonstrate that the antidepressant efficacy of St John's wort (Hypericum) is comparable to that of tricyclic antidepressants such as imipramine. Onset of efficacy of these drugs occurs after several weeks of treatment. Therefore, we used in situhybridization histochemistry to examine in rats the effects of short-term (2 weeks) and...

The brain's response to a direct immune challenge was examined by in situ hybridization histochemistry. Lipopolysaccharide (bacterial endotoxin) injected acutely into rat striatum induced mRNA expression for inhibitory factor kappaBalpha, interleukin (IL)-1beta, tumor necrosis factor-alpha, IL-6, IL-12 p35, inducible nitric oxide synthase, IL-1 rec...

Peripheral injection of bacterial endotoxin lipopolysaccharide (LPS) induces brain mRNA expression of the proinflammatory cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha and the cytokine-responsive immediate-early gene IkappaBalpha. Peripheral LPS also increases levels of plasma glucocorticoids. Whether the induction of Ikapp...

Peripheral injection of bacterial endotoxin lipopolysaccharide (LPS) induces brain mRNA expression of the proinflammatory cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha and the cytokine-responsive immediate-early gene IkappaBalpha. Peripheral LPS also increases levels of plasma glucocorticoids. Whether the induction of Ikapp...

Double-label in situ hybridization was used to identify the phenotypes of striatal neurons that express mRNA for cannabinoid CB(1) receptors. Simultaneous detection of multiple mRNAs was performed by combining a (35)S-labeled ribonucleotide probe for CB(1) mRNA with digoxigenin-labeled riboprobes for striatal projection neurons (preprotachykinin A,...

We sought to determine whether the fragile X mental retardation gene fmr1 is regulated in long-term potentiation (LTP) and electroconvulsive shock (ECS). In situ hybridization of fmr1 mRNA in hippocampus of rats given LTP in vivo showed no change in fmr1 mRNA levels relative to control. However, ECS induced a selective increase in fmr1 mRNA express...

We have reported previously that axonal degeneration in specific brain regions occurs in rats infected with the parasite Trypanosoma brucei. These degenerative changes occur in spatiotemporal association with over-expression of pro-inflammatory cytokine messenger RNAs in the brain. To test how aspirin-like anti-inflammatory drugs might alter the di...

Parasynaptic communication, also termed volume transmission, has been suggested as an important means to mediate information transfer within the central nervous system. The purpose of the present study was to visualize by autoradiography the available channels for fluid movement within the extracellular space following injection of the inert extrac...

Overproduction of proinflammatory cytokines in the brains of transgenic animals causes brain pathology. To investigate the relationship between brain cytokines and pathology in the brains of animals with adult-onset, pathophysiologically induced brain cytokine expression, we studied rats infected with the parasite Trypanosoma brucei. Several weeks...

Overproduction of proinflammatory cytokines in the brains of transgenic animals causes brain pathology. To investigate the relationship between brain cytokines and pathology in the brains of animals with adult-onset, pathophysiologically induced brain cytokine expression, we studied rats infected with the parasite Trypanosoma brucei. Several weeks...

Mu and delta opioid receptors were labeled in enkephalin knockout mice by quantitative autoradiography. Discrete, large increases (100-300%) were found in limbic forebrain structures for mu binding and striatum and pallidum for delta binding. The up-regulation of opioid receptors may reflect a form of 'denervation supersensitivity. ' The receptor u...

Delta9-Tetrahydrocannabinol (Delta9-THC), the major psychoactive ingredient in preparations of Cannabis sativa (marijuana, hashish), elicits central nervous system (CNS) responses, including cognitive alterations and euphoria. These responses account for the abuse potential of cannabis, while other effects such as analgesia suggest potential medici...

In situ hybridization histochemistry was used to show the distribution of messenger RNA for central cannabinoid CB 1 receptors in dorsal root ganglia of the rat. CB1 messenger RNA was highly expressed in neuronal subpopulations of rat dorsal root ganglia. The phenotypes of neurons that express messenger RNA for CB1 were subsequently examined by com...

In vitro receptor binding and quantitative autoradiography were used to assess the pre- and postsynaptic distribution of cannabinoid receptors in the cervical dorsal horn of the rat spinal cord. An extensive unilateral dorsal rhizotomy was performed across seven or eight successive spinal segments from C3 to T1 or T2. The densities of cannabinoid a...

Cannabinoids modulate nociceptive processing through central and peripheral mechanisms. The present study was conducted to evaluate axonal flow of cannabinoid receptors from the dorsal root ganglion to the periphery and to identify the putative involvement of CB1 and/or CB2 receptor subtypes. The sciatic nerve was tightly ligated to dam the flow of...

Although it is generally accepted that pro-inflammatory cytokines produced by cells of the central nervous system play important roles in the communication between the central nervous system and the immune system during sepsis, it is not clear whether these cytokines are produced in the brain under subseptic conditions. In this study, we used in si...

Brain cells responsive to a peripheral immune challenge, identified by in situ hybridization of c-fosmRNA following intravenous administration of the proinflammatory cytokine interleukin-1β (IL-1) or sterile saline, were investigated at 0.5, 1, and 3 hours postinjection in rats. Doses of IL-1 ranged from 0.05 to 10 μg/kg; induction of c-fos mRNA oc...

In vitro receptor binding and quantitative autoradiography were used to determine whether cannabinoid receptors in rat lumbar spinal cord are localized to the central terminals of nociceptive primary afferents. Rats were treated as neonates with capsaicin to destroy sensory C-fibers. The densities of cannabinoid and mu opioid receptors in the spina...

Inducible cyclooxygenase 2 (COX 2) converts arachidonic acid to prostaglandins, which are thought to mediate various peripheral lipopolysaccharide (LPS)-induced central effects, including generation of fever and activation of the hypothalamic-pituitary-adrenal axis. To localize prostaglandin production in the brain following peripheral LPS administ...

This study examined the role of the area postrema (AP) in transducing peripheral immune signals, represented by intravenous (i.v.) interleukin-1beta (IL-1), into neuroendocrine responses. The AP, a circumventricular organ with a leaky blood-brain barrier, lies adjacent to the nucleus of the solitary tract (NTS) in the medulla. The AP was removed by...

The inflammatory cytokine interleukin-1 has been implicated as a mediator of many centrally controlled responses, such as fever and increased activity of the hypothalamic-pituitary-adrenal axis, after systemic infections. To identify the neuroanatomical loci of brain interleukin-l-producing cells during infection, we investigated interleukin-1β mes...

In this study we investigate the mRNA expression of inhibitory factor kappaBalpha (IkappaBalpha) in cells of the rat brain induced by an intraperitoneal (i.p.) injection of lipopolysaccharide (LPS). IkappaB controls the activity of nuclear factor kappaB, which regulates the transcription of many immune signal molecules. The detection of IkappaB ind...

Antidepressant drugs have in common a delayed onset of clinical efficacy. In rats, long-term, daily administration of four different types of clinically effective antidepressant drugs results in decreased corticotropin releasing hormone (CRH) mRNA expression levels in the hypothalamic paraventricular nucleus (PVN). Because a subpopulation of neurop...

Induction of long-term potentiation (LTP) in the dentate gyrus of awake rats triggered a rapid (2 hour) elevation in tyrosine kinase receptor (trkB and trkC) gene expression and a delayed (6-24 hour) increase in brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) gene expression. Depending on the mRNA species, LTP induction led to hi...

The possible role that the hypothalamic arcuate nucleus might play in mediating the increase in paraventricular nucleus corticotropin-releasing hormone mRNA levels following adrenalectomy was investigated in two series of experiments. In the first series in situ hybridization histochemistry was used to quantify levels of eight accurate nucleus neur...

Expression of neuropeptide messenger RNAs in striatal neurons was studied in post mortem human brain tissue by the use of in situ hybridization histochemistry. Clusters of cells expressing high levels of prodynorphin messenger RNA, and less strikingly, preprotachykinin messenger RNA, were prominent in the caudate nucleus and were present but less p...

The distribution and density of cannabinoid receptor binding and messenger RNA expression in aged human brain were examined in several forebrain and basal ganglia structures. In vitro binding of [3H]CP-55,940, a synthetic cannabinoid, was examined by autoradiography in fresh frozen brain sections from normal aged humans (n = 3), patients who died w...

Selective neuronal vulnerability is a key feature of the neuropathology of Huntington's disease. We used [3H]CP-55,940, a synthetic cannabinoid, to label cannabinoid receptors in tissue sections from individuals dying with Huntington's disease and from normal control subjects. The density of cannabinoid receptors in striatum and pallidum was measur...

Electroconvulsive shock (ECS) is a highly effective therapy for the treatment of major depression, but its mechanisms of action are not known. We report that repeated ECS in rats produces enduring changes in two clinically relevant stress-responsive brain systems: (a) the hypothalamic-pituitary-adrenal axis regulated by corticotropin-releasing horm...

This study was designed to examine the mechanisms by which systemic interleukin-1 affects neuroendocrine systems in the brain. Intraperitoneal injections of interleukin-1 beta (1.25 micrograms/rat) were administered to rats. One or three hours after injection, the expression levels of the immediate-early gene c-fos and of genes for several neuropep...

This study was designed to examine the mechanisms by which systemic interleukin-1 affects neuroendocrine systems in the brain. Intraperitoneal injections of interleukin-1 beta (1.25 micrograms/rat) were administered to rats. One or three hours after injection, the expression levels of the immediate-early gene c-fos and of genes for several neuropep...

[3H]CP-55,940, a high-affinity cannabinoid receptor ligand, was used for in vitro binding and autoradiography in peripheral tissues in the rat. Specific cannabinoid receptor binding was found to be restricted to components of the immune system, i.e., spleen, lymph nodes and Peyer's patches. Displacement studies showed that this binding is identical...

A recent study demonstrated that hypothalamic lesions induced by goldthioglucose (GTG) in mice produced an increase in neuronal immunoreactivity for neuropeptide Y (NPY) in the hypothalamic arcuate nucleus. Since NPY is a potent stimulator of feeding, this increase represented a potential explanation for the hyperphagia seen after GTG lesions. To e...

The active ingredient of marijuana is (-)-delta 9-tetrahydrocannabinol (delta 9-THC). delta 9-THC and other natural and synthetic cannabinoids such as CP-55,940 inhibit spontaneous activity and produce catalepsy in animals in a receptor-mediated fashion. Tolerance develops to the motor effects of delta 9-THC after repeated administration. To test t...

Molecular changes in the neostriatum of human subjects who died with a history of cocaine abuse were revealed in discrete cell populations by means of the techniques of in situ hybridization histochemistry and in vitro receptor binding and autoradiography. Cocaine subjects had a history of repeated cocaine use and had cocaine and/or cocaine metabol...

The acute and long-term effects of a single injection of psychomotor stimulants (amphetamine (1.5 mg/kg i.p.), cocaine (30 mg/kg i.p.) and GBR 12909 (10 mg/kg i.p.)) were studied with in situ hybridization histochemistry to assess alterations in the mRNA expression of enkephalin, dynorphin and substance P in the striatum. The greatest alterations o...

In situ hybridization histochemistry was used to localize and quantify the effects of acute and repeated immobilization stress on mRNA levels of tyrosine hydroxylase (TH) in catecholaminergic neurons in the locus ceruleus and substantia nigra and on mRNA levels of relevant markers of the hypothalamic-pituitary-adrenal axis, namely corticotropin-rel...

Various classes of antidepressant drugs with distinct pharmacologic actions are differentially effective in the treatment of classic melancholic depression--characterized by pathological hyperarousal and atypical depression--associated with lethargy, hypersomnia, and hyperphagia. All antidepressant agents exert their therapeutic efficacy only after...

The hippocampus appears to be an important modulator of the negative feedback effects of glucocorticoids on the hypothalamic-pituitary-adrenal axis. It is not known if hippocampal subfields CA1-4 or the dentate gyrus differentially alter gene expression of corticotropin-releasing hormone (CRH) in the paraventricular nucleus (PVN) of the hypothalamu...

We used the autoradiographic tract‐tracing method to define the amygdaloid projection fields after injecting ³ H‐amino acids into individual thalamic nuclei in the rat. The parvicellular division of the ventroposterior nucleus, the thalamic taste relay, projected lightly to the central and lateral amygdaloid nuclei. The central medial, interanterom...