Opioids are the most widely used drugs for long-term pain management, but their use is limited by the development of antinociceptive tolerance. The present study investigated the role of ceramide production via acid sphingomyelinase (ASM) activation in the periaqueductal gray region, a brain region implicated in opioid analgesia and tolerance. Morphine treatment was found using immunohistochemistry to increase ASM expression and intracellular ceramide in the periaqueductal gray 30 min after acute injection (10 mg/kg). The effects of acute morphine treatment on ASM expression and ceramide generation in the periaqueductal gray region were completely blocked by pretreatment with naloxone and by silencing the ASM gene by plasmid-mediated transfection of ASM shRNA. In chronic morphine pellet-implanted mice, ASM expression and ceramide generation in the periaqueductal gray region were also significantly increased. Functionally, selective silencing of the ASM gene by local ASM shRNA transfection reduced the analgesic response to acute morphine, but the data regarding the ASM shRNA effect on development of antinociceptive tolerance were inconclusive. These data provide evidence that ASM activation and ceramide generation in the periaqueductal gray region is importantly involved in the antinociceptive mechanism of morphine.
Acid sphingomyelinase; ceramide; periaqueductal gray region; morphine tolerance; mu opioid receptor
Axonal branches from a subset of neurons in cerebral cortical layer 6 innervate both cortical layer 4 and the thalamus. As such, these neurons are poised to modulate thalamocortical transmission at multiple forebrain sites. Here, we examined the functional organization of the layer 6 intracortical projections in auditory, somatosensory and visual cortical areas using an optogenetic approach to specifically target these neurons. We characterized the anatomical and physiological organization of these projections using laser-scanning photostimulation to functionally map the elicited postsynaptic responses in layer 4. We found that these responses originated from regions over 1 mm in width, eliciting short-term facilitating responses. These results indicate that intracortical modulation of layer 4 occurs via widespread layer 6 projections in each sensory cortical area.
cortex; thalamus; layer 6; layer 4; optogenetics; cre-lox recombination; auditory; somatosensory; visual
Migraine has been traditionally considered a non-progressive, paroxysmal disorder with no brain abnormalities between attacks. We used diffusion tensor imaging to examine interictal diffusion properties of the brains of migraineurs with aura, migraineurs without aura and matched healthy controls. Areas of lower fractional anisotropy (FA) were present in migraineurs along the thalamocortical tract. In addition, migraineurs with aura had lower FA in the ventral trigeminothalamic tract, and migraineurs without aura had lower FA in the ventrolateral periaqueductal gray matter. Our results indicate the presence of permanent interictal changes in migraineurs, pointing to an effect of migraine on the trigeminal somatosensory and modulatory pain systems.
Migraine; DTI; trigeminal somatosensory system; periacqueductal grey; imaging; brain
Reading difficulties appear to be related to a phonological deficit that has its origin in poor speech perception. As such, disabled readers may use contextual cues to compensate for their weak speech perception abilities. We compared good and poor readers, 7–13 years, on auditory perception of words varying in phonological contrast, in congruent vs. incongruent sentence contexts. Both groups did worse in the phonologically similar than in the phonologically dissimilar incongruent condition. Magnetoencephalography revealed differential activation between the groups as a function of phonological contrast in left superior temporal gyrus between 200–300 ms, suggesting that poor readers may have processed phonologically similar incongruent stimuli as congruent. The results are consistent with a phonological account of reading disability.
Magnetoencephalography; PMN; N400; dyslexia; reading impairment
The basic helix–loop–helix factor Math5 (Atoh7) is critical for the determination of retinal ganglion cell (RGC) fate in mice. Recently, genome-wide association studies have identified the ATOH7 locus as a major determinant of variation in the human optic disc area, which is directly correlated with the RGC number. These studies suggest that the level of Math5 expression may determine the ultimate number of RGCs. To test this hypothesis, we systematically compared optic nerve area and RGC axon number in C57BL/6J congenic Math5+/– and +/+ mice at young adult and neonatal ages by transmission electron microscopy. Optic disc area and RGC abundance were not significantly different in adults, but heterozygotes had thinner optic nerves and 25–30% fewer RGCs at birth than wild-type littermates (P < 0.05). Our results suggest that Math5 dosage is important for the genesis, but not the ultimate number, of RGCs. Our findings highlight the importance of ganglion cell culling as a compensatory mechanism for retinal homeostasis, and support a quantitative role for Math5 in RGC specification.
apoptosis; Atoh7; culling; glaucoma; genome-wide association studies; Math5; neurogenesis; optic disc area; optic nerve; retinal ganglion cell
Converging evidence suggests too few activation-ready N-methyl-d-aspartic acid (NMDA) receptor complexes in the postsynaptic density in schizophrenia. Postsynaptic density protein 95 (PSD95), Synaptic GTPase-activating protein (SynGAP), and Multiple PDZ domain protein (MUPP1) are integral components of the NMDA receptor signaling complex, and help facilitate signaling, trafficking, and stabilization. We hypothesized that deficits involving these molecules may contribute to the pathophysiology of schizophrenia. To test our hypothesis, we measured protein expression of PSD95, SynGAP, and MUPP1 in the anterior cingulate cortex and dorsolateral prefrontal cortex. We found decreased PSD95 expression in the anterior cingulate cortex. Antipsychotic medication analyses showed decreased SynGAP expression in the anterior cingulate cortex in patients off medication when analyzed against our comparison group. These data suggest that NMDA receptor complex formation, localization, and downstream signaling may be abnormal in schizophrenia.
MUPP1; N-methyl-d-aspartic acid receptor; PSD95; schizophrenia; SynGAP
London taxi drivers are renowned for their navigation ability, spending a number of years acquiring ‘The Knowledge’ of London’s complex layout and having to pass stringent examinations to obtain an operating licence. In several studies, this navigation skill has been associated with increased posterior but also decreased anterior hippocampal grey matter volume. Neuropsychologically, gain and loss has also been documented in taxi drivers; while very skilled at navigation in London, they are significantly poorer than controls at learning and recalling new object-location associations. Here we tested a group of London taxi drivers and matched control participants on this object-location associations task, while also submitting them to a battery of challenging anterograde associative memory tests involving verbal, visual and auditory material both within and across modalities. Our aim was to assess whether their difficulty in previous studies reflected a general problem with associative memory, or was restricted to the spatial domain. We replicated previous findings of poor learning and memory of object-location associations. By contrast, their performance on the other anterograde associative memory tasks was comparable to controls. This resolves an outstanding question in the memory profile of London taxi drivers following hippocampal plasticity, and underlines the close relationship between space and the hippocampus.
hippocampus; navigation; taxi drivers; associative memory; space
The involvement of matrix metalloproteinase (MMP) 9 in methamphetamine-induced neurotoxicity was evaluated. Injection of mice with stimulant or toxic doses of methamphetamine up regulated MMP9 gene expression in the brain within 5 min. By 24 h, MMP9 gene expression returned to control levels in the stimulant-treated mice, but remained elevated in animals exposed to toxic doses of methamphetamine. Reductions in striatal dopamine levels, a marker of methamphetamine neurotoxicity, developed 1–7 days following methamphetamine exposure, but were not accompanied by concomitant changes in MMP9 gene expression. In MMP9 knock out mice, methamphetamine retained its ability to elicit neurotoxicity. The data suggest that MMP9 expression does not contribute to methamphetamine-induced neurotoxicity, and may instead be involved in remodeling of the nervous system.
MMP9; methamphetamine; neurotoxicity; sensitization
Murine transgenic models of Alzheimer’s disease (Tg-AD) have been useful to analyze the contribution of β-amyloid precursor protein (βAPP), Aβ42 peptide deposition, and the proinflammatory mechanisms that characterize Alzheimer-type neuropathology. In this report, we have studied the levels of βAPP, Aβ40 and Aβ42 peptide, as well as the innate immune and inflammatory response-regulator complement factor H in the brain and retina in four different Tg-AD models including Tg2576, PSAPP, 3xTg-AD, and 5xFAD. Aged, symptomatic 5xFAD mice showed the highest retinal abundance of Aβ42 peptides and the highest deficits in complement factor H. This may be a useful model to study the mechanisms of amyloidmediated inflammatory degeneration. The superior colliculus and retina obtained from late-stage Alzheimer’s disease revealed upregulated amyloidogenic and inflammatory signaling along the anteroposterior axis of the retinal-primary visual cortex pathway.
5xFAD; age-related macular degeneration; Alzheimer’s disease; inflammatory neurodegeneration; miRNA-146a; retina; Tg2576; transgenic models of Alzheimer’s disease
MicroRNAs are important in central nervous system development, functioning, and pathophysiology. Here we demonstrate that increasing levels of microRNA 320 (miR-320) for 3 days markedly increases neurite length and at 4 days reduces total cell number in N2A cells. In silico analysis of possible miR-320 targets identified cAMP-regulated phosphoprotein-19 kDa (ARPP-19) and semaphorin 3a (Sema3a) as potential targets that could be involved. ARPP-19 was validated by demonstrating reduced mRNA and protein levels when miR-320 was overexpressed, while miR-320 had no effect on Sema3a expression. ARPP-19 is known to inhibit protein phosphatase-2A (PP2A) activity, which inhibits mitosis and induces neurite outgrowth, making this the likely mechanism. Thus increased levels of miR-320 leads to decreased levels of ARPP-19, increased neurite length, and fewer total cells. These data suggest that miR-320 could play a role in neuronal development and might be a target to enhance neuronal regeneration following injury.
microRNA; neurite outgrowth; ARPP-19; PP2A
Brain arteriovenous malformation (BAVM), a rare but important cause of intracranial hemorrhage, has increased angiogenesis and inflammation as key components of the nidus of abnormal vessels and stroma that form the resected surgical specimen. Accordingly, vascular endothelial growth factor (VEGF) and transforming growth factor-β (TGFβ) have both been implicated in BAVM pathology for their pro-angiogenic and vascular-regulating roles. The c-terminal fragment of the extracellular matrix component perlecan (domain V, DV) has been shown to be increased and to, via the α5β1 integrin, increase VEGF levels in and around areas of cerebral ischemic injury, another pro-angiogenic condition. We sought to determine whether the concentrations of DV, DV’s proangiogenic receptor α5β1 integrin, or DV’s anti-angiogenic receptor α2β1 integrin are elevated in human BAVM tissue. DV levels were increased in BAVM compared to control brain tissue from epileptic resection, as was α5β1 integrin. Additionally, α5β1 integrin was preferentially increased and localized to endothelial cells compared to α2β1 integrin. VEGF and TGFβ levels were also increased in BAVM compared to control tissue. Furthermore, increases in all components were strongly correlated. Excessive generation of pro-angiogenic DV in BAVM suggests that DV may participate in its pathology and may represent a future therapeutic target.
Arteriovenous Malformation; AVM
ErbB4has emerged as a leading susceptibility gene for schizophrenia but the function of the ErbB4 receptor in the adult brain is unknown. Here we show in the adult hippocampus that long-term potentiation (LTP) of transmission at Schaffer-collateral CA1 synapses was markedly enhanced in mutant mice lacking ErbB4. Concordantly, LTP was enhanced by acutely blocking ErbB4 in wild type animals, indicating that ErbB4 activity constitutively suppresses LTP. Moreover, increasing ErbB4 signaling further suppressed LTP. By contrast, altering ErbB4 activity did not affect basal synaptic transmission or short-term facilitation. Our findings suggest that cognitive deficits in schizophrenia may be a consequence of hyperfunction of ErbB4 signaling leading to suppressed glutamatergic synaptic plasticity, thus opening new approaches for treatment of this disorder.
PMID: 18185097 CAMSID: cams2735
ErbB4; transgenic mouse; neuregulin; Schaffer collateral-CA1 synapses; long-term potentiation; theta burst stimulation; synaptic plasticity; paired-pulse facilitation
In women, pain symptoms and nociceptive thresholds vary with reproductive cycle suggesting the role of estrogen receptors (ERs) in modulating nociception. Our previous data strongly suggest interaction between ERs and ATP-induced purinergic (P2X3) as well as ERs and capsaicin-induced vanilloid (TRPV1) receptors at the level of dorsal root ganglion (DRG) neurons. In this study we investigated the expression of P2X3 and TRPV1 receptors by western blotting and immunohistochemistry in lumbosacral DRGs from wild type, estrogen receptor-α and estrogen receptor-β knockout mice. We found a significant decrease for both P2X3 and TRPV1 in ERαKO and ERβKO. This phenomenon was visualized in L1, L2, L4, and L6 levels for P2X3 receptors and in L1, L2, and S2 levels for TRPV1 receptors. This tan interaction between P2X3/TRPV1 and ERs expression in sensory neurons may represent a novel mechanism that can explain sex differences in nociception observed in clinical practice. The DRG is an important site of visceral afferent convergence and cross-sensitization and potential target for designing new anti-nociceptive therapies.
DRG; P2X3; TRPV1; ERα; ERβ; mouse
Alterations in glutamatergic neurotransmission are thought to be involved in several psychiatric disorders, including schizophrenia. Equlibrative nucleoside transporter 1 (ENT1) regulates glutamate levels by regulating excitatory amino acid transporter expression and activity in the brain. In this study, we investigated whether ENT1 is abnormally expressed in the brain of elderly patients with schizophrenia. We measured protein expression of ENT1 in the superior temporal gyrus (STG) and anterior cingulate cortex (ACC) in patients with schizophrenia (STG, n = 22; ACC, n = 34) and a comparison group (STG, n = 24; ACC, n = 29). We found decreased ENT1 expression in the superior temporal gyrus in patients with schizophrenia, supporting the hypothesis of altered glutamate transport in this illness.
Equlibrative nucleoside transporter 1 (ENT1); schizophrenia; glutamate; excitatory amino acid transporter (EAAT); adenosine
The overall volume of the brain has been found to be under relatively strong genetic control, but the relative strength of genetic and environmental factors on between-person variations in regional cortical thickness in adolescence is still not well understood. Here, we analyzed structural MRI data from 108 14-year-old healthy twins (54 females/54 males) to determine the relative contributions of genes and the environment toward regional variations in gray matter thickness across the cortex. After extracting cortical thickness values at a high spatial resolution, an A/C/E structural equation model that divides the variations into additive genetic (A), shared (C), and unique (E) environmental components was fitted. There was considerable regional variability in the magnitude of genetic influences on cortical thickness after controlling for sex. Regions with genetic contributions of greater than 80% were observed in the prefrontal cortex, predominantly in the bilateral dorsolateral and mesial superior frontal regions. No region showed prominent shared environmental influences, but unique environmental influences of over 80% were found in parietal association regions. The genetic variance for cortical thickness in adolescents in prefrontal regions overlapped with previous findings in adults. However, the unique environmental effects observed in multimodal parietal association cortices with converging inputs from visual, auditory, somatosensory regions, and neighboring secondary association cortices suggest that these regional variations are more shaped by experience and could form targets for early interventions in youth with behavioral disorders.
adolescent twins; cortical thickness; heritability; MRI
Linguistic and musical pitch provide an analytic window to evaluate how neural representations of important pitch attributes of a sound undergo transformation from early sensory to later cognitive stages of processing in the human brain, and how pitch-relevant experience shapes these representations. These pitch attributes are shaped differentially depending upon their functional relevance to a listener. Neural encoding of pitch-relevant information is shaped by the perceptual salience of domain-specific features at subcortical (auditory brainstem) as well as cortical stages of processing. The emergence of a functional ear asymmetry in the neural encoding of pitch-relevant information at a lower sensory processing level supports the view that local as well as feedforward and feedback mechanisms are involved in pitch-relevant processing. A theoretical framework for a neural network is proposed involving coordination between local, feedforward, and feedback components that can account for experience-induced enhancement of pitch representations at multiple levels of the auditory pathway.
auditory brainstem; speech perception; pitch; frequency following response (FFR); iterated rippled noise (IRN); mismatch negativity (MMN); language; music; experience-dependent plasticity; functional ear asymmetry
Recent studies show that electrophysiological markers of auditory processing such as the cortical 100ms response (M100) and the mismatch field (MMF), derived from magnetoencephalography (MEG), might be used to identify children with autism spectrum disorders - M100 peak latency - and to stratify children with autism according to the degree of language impairment – mismatch field peak latency.
The present study examined the latencies of right superior temporal gyrus M100 and mismatch field in a cohort of children and young adolescents with specific language impairment (n=17), in comparison to age and non-verbal IQ matched typically developing controls (n=21). Neither group showed symptoms associated with autism.
Whereas M100 latency (reflecting early auditory processing) did not distinguish controls from children with specific language impairment, the later “change detection” mismatch field response was significantly delayed (by >50ms) in the specific language impairment group. Linear discriminant analysis confirmed the role of mismatch field latency (92%) but not M100 latency (8%) in distinguishing groups.
Present results add support to the claim that a delayed M100 is specific to autism spectrum disorders (with relative independence of degree of language impairment) and that a delayed mismatch field reflects an abnormality more generally associated with language impairment, suggesting that mismatch field delay in the present specific language impairment group and previously reported in autistic children with language impairment may be indicative of a common neural system dysfunction.
Language impairment; magnetoencephalography; mismatch field
B7-H1 is a recently discovered immunoresistance protein that is regulated post-transcriptionally after PTEN loss in malignant glioma, a deadly form of brain tumor. Here, the impact of gamma interferon mediated activation of B7-H1 was investigated in glioblastoma patients with PTEN loss. Lymphocytes and T-cells were selected for apoptosis assays after 1:1 co-culture with autologous glioma cells. Gamma interferon treatment of PTEN deficient tumors resulted in superinduction of B7-H1 protein that correlated with increased T-cell apoptosis, an effect dependent upon activation of the PI3Kinase pathway. The combination of PTEN loss and gamma interferon exposure in glioblastoma patients results in an exceptionally immunoresistant phenotype that may negate adaptive immunity through induction of T-cell apoptosis.
B7-H1; PD-L1; Interferon gamma; Glioma; Immunoresistance; Immune evasion
ERP studies of rhyme judgments in alphabetic languages show that non-rhyming word pairs elicit a larger negative-going wave peaking 450 ms post stimulus onset than rhyming word pairs. We use Chinese characters to explore the extent to which this N450 rhyming effect reflects phonological processing. Using Chinese provides an advantage over alphabetic scripts because rhyming characters can have non-overlapping orthographic forms, something not possible in alphabetic scripts. We recorded ERPs while Chinese speakers made rhyme judgments to Chinese and English words. An N450 effect was observed in both languages. Moreover, the N450 effects exhibited in the two languages were correlated. The results support the phonological account of the N450 effect and indicate that similar phonological operations are involved in different languages.
ERPs; N450; Chinese; phonological processing; rhyme judgment
We examined male and female adolescents (8–18 years of age) that were scanned with structural brain MRI and looked for a correlation between volume of the right or the left amygdala and parent-reported ability of emotional control. A sex difference was found in the correlation between emotional control and the corrected volume of the left amygdala (that is the amygdala volume adjusted for total cranial volume). In girls, smaller left amygdala volumes were associated with better emotional control. In boys, larger left amygdala volumes were associated with better emotional control. These findings suggest that healthy girls and boys show a difference in the correlation between parental reports of emotional control and the left amygdala volume.
adolescents; amygdala volume; MRI
Cumulating evidence has demonstrated that mu opioid receptor (MOR) agonists promote spinal glial activation, lead to synthesis and release of proinflammatory cytokines and chemokines, and contribute to opioid-induced hyperalgesia and development of opioid tolerance and dependence. However, whether these MOR agonists directly or indirectly act on spinal cord astrocytes and microglial cells in vivo is unclear. In the present study, by combining the techniques of in situ hybridization of MOR mRNA with immunohistochemistry of GFAP (an astrocyte marker) and Iba1 (a microglial marker), we examined expression and distribution of GFAP, Iba1, and MOR mRNA in the spinal cord of rats under chronic morphine tolerance conditions. Twice daily intrathecal injections of morphine for 7 days reduced morphine analgesic effect and increased both GFAP and Iba1 immunostaining densities in spinal cord. Unexpectedly, neither GFAP nor Iba1 colocalized with MOR mRNA in spinal cord cells. Our findings indicate that MOR expression is absent from spinal cord astrocytes and microglia, suggesting that these cell types are indirectly activated by MOR agonists under chronic opioid tolerance conditions.
mu opioid receptor; astrocyte; microglial cells; expression; spinal cord; morphine tolerance
Women with estrogen receptor (ER) positive breast cancer, who are treated with the ER blocker, tamoxifen, have an increased risk of depression. Trilostane, a 3β-hydroxysteroid dehydrogenase inhibitor, is now being used to treat tamoxifen-insensitive breast cancer. In-vitro assays show that trilostane may have actions through ERβ. Results of in-vivo research shows that actions at ERβ may underline some antidepressant effects of estrogen. We hypothesized that trilostane may exert antidepressive effects in the forced swim in part due to actions through ERβ. Trilostane (25 mg/kg, intraperitoneally), compared with vehicle, had significant antidepressant-like effects but only when administered to wild-type, not ERβ knockout, mice. Thus, actions of trilostane through ERβ may underlie some of its antidepressant-like effects.
3α-hydroxy-5α-pregnan-20-one; breast cancer; depression; estrogen; tamoxifen