Bidirectional modulation of hyperalgesia via the specific control of excitatory and inhibitory neuronal activity in the ACC

Neurons in the anterior cingulate cortex (ACC) are assumed to play important roles in the perception of nociceptive signals and the associated emotional responses. However, the neuronal types within the ACC that mediate these functions are poorly understood. In the present study, we used optogenetic techniques to selectively modulate excitatory pyramidal neurons and inhibitory interneurons in the ACC and to assess their ability to modulate peripheral mechanical hypersensitivity in freely moving mice. We found that selective activation of pyramidal neurons rapidly and acutely reduced nociceptive thresholds and that this effect was occluded in animals made hypersensitive using Freund's Complete Adjuvant (CFA). Conversely, inhibition of ACC pyramidal neurons rapidly and acutely reduced hypersensitivity induced by CFA treatment. A similar analgesic effect was induced by activation of parvalbumin (PV) expressing interneurons, whereas activation of somatostatin (SOM) expressing interneurons had no effect on pain thresholds. Our results provide direct evidence of the pivotal role of ACC excitatory neurons, and their regulation by PV expressing interneurons, in nociception. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13041-015-0170-6) contains supplementary material, which is available to authorized users

Effect of ablated hippocampal neurogenesis on the formation and extinction of contextual fear memory

Newborn neurons in the subgranular zone (SGZ) of the hippocampus incorporate into the dentate gyrus and mature. Numerous studies have focused on hippocampal neurogenesis because of its importance in learning and memory. However, it is largely unknown whether hippocampal neurogenesis is involved in memory extinction per se. Here, we sought to examine the possibility that hippocampal neurogenesis may play a critical role in the formation and extinction of hippocampus-dependent contextual fear memory. By methylazoxymethanol acetate (MAM) or gamma-ray irradiation, hippocampal neurogenesis was impaired in adult mice. Under our experimental conditions, only a severe impairment of hippocampal neurogenesis inhibited the formation of contextual fear memory. However, the extinction of contextual fear memory was not affected. These results suggest that although adult newborn neurons contribute to contextual fear memory, they may not be involved in the extinction or erasure of hippocampus-dependent contextual fear memory

Mechanism and treatment for learning and memory deficits in mouse models of Noonan syndrome.

In Noonan syndrome (NS) 30-50% of subjects show cognitive deficits of unknown etiology and with no known treatment. Here, we report that knock-in mice expressing either of two NS-associated mutations in Ptpn11, which encodes the nonreceptor protein tyrosine phosphatase Shp2, show hippocampal-dependent impairments in spatial learning and deficits in hippocampal long-term potentiation (LTP). In addition, viral overexpression of an NS-associated allele PTPN11(D61G) in adult mouse hippocampus results in increased baseline excitatory synaptic function and deficits in LTP and spatial learning, which can be reversed by a mitogen-activated protein kinase kinase (MEK) inhibitor. Furthermore, brief treatment with lovastatin reduces activation of the GTPase Ras-extracellular signal-related kinase (Erk) pathway in the brain and normalizes deficits in LTP and learning in adult Ptpn11(D61G/+) mice. Our results demonstrate that increased basal Erk activity and corresponding baseline increases in excitatory synaptic function are responsible for the LTP impairments and, consequently, the learning deficits in mouse models of NS. These data also suggest that lovastatin or MEK inhibitors may be useful for treating the cognitive deficits in NS

Coexistence of Two Forms of LTP in ACC Provides a Synaptic Mechanism for the Interactions between Anxiety and Chronic Pain

SummaryChronic pain can lead to anxiety and anxiety can enhance the sensation of pain.　Unfortunately, little is known about the synaptic mechanisms that mediate these re-enforcing interactions. Here we characterized two forms of long-term potentiation (LTP) in the anterior cingulate cortex (ACC); a presynaptic form (pre-LTP) that requires kainate receptors and a postsynaptic form (post-LTP) that requires N-methyl-D-aspartate receptors. Pre-LTP also involves adenylyl cyclase and protein kinase A and is expressed via a mechanism involving hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Interestingly, chronic pain and anxiety both result in selective occlusion of pre-LTP. Significantly, microinjection of the HCN blocker ZD7288 into the ACC in vivo produces both anxiolytic and analgesic effects. Our results provide a mechanism by which two forms of LTP in the ACC may converge to mediate the interaction between anxiety and chronic pain

Social Isolation Selectively Increases Anxiety in Mice without Affecting Depression-like Behavior

It is hypothesized that a number of environmental factors affect animals' behavior. Without controlling these variables, it is very hard for researchers to get not only reliable, but replicable data from various behavioral experiments testing animals' cognitive as well as emotional functions. For example, laboratory mice which had restricted environment showed different synaptic potentiation properties with wild mice (Zhao MG et al., 2009). While performing behavioral experiments, however, it is sometimes inevitable that the researcher changes the animals' environments, as by switching the cages in which experimental animals are housed and separating animals raised together into small experimental groups. In this study, we investigated the effect of environmental changes on mice's emotional behaviors by socially isolating them or reducing the size of their cage. We found that social isolation selectively increases the animals' levels of anxiety, while leaving depression-like behaviors unchanged. On the other hand, alteration of the housing dimensions affected neither their anxiety levels nor their depression-like behaviors. These results suggest that environmental variables may have a prominent impact on experimental animals' emotional behaviors and possibly their psychological states, leading to bias in the behavioral data produced from experiments

Conditional knock out of transcription factor CTCF in excitatory neurons induces cognitive deficiency

CCCTC-binding factor (CTCF) is a transcription factor that is involved in organizing chromatin structure. A reduction of CTCF expression is known to develop distinct clinical features. Furthermore, conditional knock out (cKO) study revealed reactive gliosis of astrocytes and microglia followed by age-dependent cell death in the excitatory neurons of CTCF cKO mice. To assess the cognitive ability in CTCF cKO mice of over 20 weeks of age, we examined pairwise discrimination (PD), PD reversal learning (PDr), and different paired-associate learning (dPAL) tasks using a touch screen apparatus. We found cognitive impairment in dPAL touch screen tests, suggesting that prolonged Ctcf gene deficiency results in cognitive deficits.Supported by the National Research Foundation (NRF) through grants funded by the Korean government (MSIP) [NRF-2019R1F1A1063932] to K.L. and [NRF-2012R1A3A1050385] to B.K.K., and by LOreal Korea-UNESCO Women in Science fellowship and LOreal-UNESCO Rising Talent Award to N.K.Y

??-Adrenergic signaling is required for the induction of a labile state during memory reconsolidation

Memory reconsolidation is the process by which previously consolidated memories reenter a labile state through reactivation of the memory trace and are actively consolidated through de novo protein synthesis. Although extensive studies have shown that ??-adrenergic signaling plays a critical role in the restabilization of reactivated memory, its role in the destabilization of long-term memory is not well-studied. In this study, we found that membrane excitability increased in hippocampal CA1 neurons immediately after the retrieval of contextual fear memory. Interestingly, this increase in membrane excitability diminished after treatment with propranolol (a ??-adrenergic receptor antagonist), an NMDA receptor antagonist, and a PKA inhibitor. In addition, we found that administration of propranolol prior to, but not after, the retrieval of fear memory ameliorated the memory impairment caused by anisomycin, indicating that inhibition of ??-adrenergic signaling blocks the destabilization of contextual fear memory. Taken together, these results indicate that ??-adrenergic signaling via NMDA receptors and PKA signaling pathway induces a labile state of long-term memory through increased neuronal membrane excitability

Bidirectional modulation of hyperalgesia via the specific control of excitatory and inhibitory neuronal activity in the ACC

Neurons in the anterior cingulate cortex (ACC) are assumed to play important roles in the perception of nociceptive signals and the associated emotional responses. However, the neuronal types within the ACC that mediate these functions are poorly understood. In the present study, we used optogenetic techniques to selectively modulate excitatory pyramidal neurons and inhibitory interneurons in the ACC and to assess their ability to modulate peripheral mechanical hypersensitivity in freely moving mice. We found that selective activation of pyramidal neurons rapidly and acutely reduced nociceptive thresholds and that this effect was occluded in animals made hypersensitive using Freund's Complete Adjuvant (CFA). Conversely, inhibition of ACC pyramidal neurons rapidly and acutely reduced hypersensitivity induced by CFA treatment. A similar analgesic effect was induced by activation of parvalbumin (PV) expressing interneurons, whereas activation of somatostatin (SOM) expressing interneurons had no effect on pain thresholds. Our results provide direct evidence of the pivotal role of ACC excitatory neurons, and their regulation by PV expressing interneurons, in nociception

Boletín de Segovia: Número 61 - 1925 mayo 22

Copia digital. Madrid : Ministerio de Cultura. Subdirección General de Coordinación Bibliotecaria, 200