Chemotherapy-induced peripheral neuropathy (CIPN) affects about 68% of patients undergoing chemotherapy, causing debilitating neuropathic pain and reducing quality of life. Cisplatin is a commonly used platinum-based chemotherapeutic drug known to cause CIPN, possibly by causing oxidative stress damage to primary sensory neurons. Metabotropic glutamate receptors (mGluRs) are widely hypothesized to be involved in pain processing and pain mitigation. Meclizine is an H1 histamine receptor antagonist known to have neuroprotective effects, including an anti-oxidative effect. Here, we used a mouse model of cisplatin-induced CIPN using male and female mice to test agonists of mGluR8 and group II mGluR as well as meclizine as interventions to reduce cisplatin-induced pain. We performed behavioral pain tests, and we imaged Ca2+ activity of the large population of DRG neurons in vivo . For the latter, we used a genetically-encoded Ca2+ indicator, Pirt-GCaMP3, which enabled us to monitor different drug interventions ...

Neuroestrogens are synthesized within the brain and regulate social behavior, learning and memory, and cognition. In song sparrows, Melospiza melodia , 17β-estradiol (17β-E2) promotes aggressive behavior, including during the non-breeding season when circulating steroid levels are low. Estrogens are challenging to measure because they are present at very low levels, and current techniques often lack the sensitivity required. Furthermore, current methods often focus on 17β-E2 and disregard other estrogens. Here, we developed and validated a method to measure four estrogens (estrone, 17β-E2, 17α-estradiol, estriol) simultaneously in microdissected songbird brain, with high specificity, sensitivity, accuracy, and precision. We used liquid chromatography tandem mass spectrometry (LC-MS/MS), and to improve sensitivity, we derivatized estrogens using 1,2-dimethylimidazole-5-sulfonyl-chloride (DMIS). The straightforward protocol improved sensitivity by 10-fold for some analytes. There is substantial regional vari...

Estrogen plays fundamental roles in nervous system development and function. Traditional studies examining the effect of estrogen in the brain have focused on the nuclear estrogen receptors (ERs), ERα and ERβ. Studies related to the extranuclear, membrane-bound G protein-coupled estrogen receptor (GPER/GPR30) have revealed a neuroprotective role for GPER in mature neurons. In this study, we investigated the differential effects of GPER activation in primary rat embryonic (E18) hippocampal and cortical neurons. Microscopy imaging, multielectrode array (MEA), and Ca2+ imaging experiments revealed that GPER activation with selective agonist, G-1, and non-selective agonist, 17β-estradiol (E2), increased neural growth, neural firing activity, and intracellular Ca2+ more profoundly in hippocampal neurons than in cortical neurons. The GPER-mediated Ca2+ rise in hippocampal neurons involve internal Ca2+ store release via activation of phospholipase C and extracellular entry via Ca2+ channels. Immunocytochemistry r...

During development, critical periods of synaptic plasticity facilitate the reordering and refinement of neural connections, allowing the definitive synaptic circuits responsible for correct adult physiology to be established. The L4-L2/3 synapses in the somatosensory cortex (S1) exhibit a presynaptic form of spike timing-dependent long-term depression (t-LTD) that probably fulfills a role in synaptic refinement. This t-LTD persists until the 4rd postnatal week in mice, disappearing thereafter. When we investigated the mechanisms underlying this maturation-related loss of t-LTD in either sex mouse slices, we found that it could be completely recovered by antagonizing adenosine type 1 receptors (A1R). By contrast, an agonist of A1R impeded the induction of t-LTD at P13-27. Furthermore, we found that the adenosine that mediated the loss of t-LTD at the end of the 4th week of development is most probably supplied by astrocytes. At more mature stages (P38-60), we found that the protocol used to induce t-LTD pro...

Zn2+ is an important contributor to ischemic brain injury, and recent studies support the hypothesis that mitochondria are key sites of its injurious effects. In murine hippocampal slices (both sexes) subjected to oxygen glucose deprivation (OGD), we found that Zn2+ accumulation and its entry into mitochondria precedes and contributes to the induction of acute neuronal death. In addition, if the ischemic episode is short (and sublethal), there is ongoing Zn2+ accumulation in CA1 mitochondria after OGD that may contribute to their delayed dysfunction. Using this slice model of sublethal OGD, we have examined Zn2+ contributions to the progression of changes evoked by OGD and occurring over 4-5 h. We detected progressive mitochondrial depolarization occurring from ∼2 h after ischemia, a large increase in spontaneous synaptic activity between 2 and 3 h, and mitochondrial swelling and fragmentation at 4 h. Blockade of the primary route for Zn2+ entry, the mitochondrial Ca2+ uniporter (with ruthenium red [RR]) o...

We studied the changes that neuronal receptive field (RF) models undergo when the statistics of the stimulus are changed from those of white Gaussian noise (WGN) to those of natural scenes (NSs), by fitting the models to multielectrode data recorded from primary visual cortex (V1) of female cats. This allowed the estimation of both a cascade of linear filters on the stimulus, as well as the static nonlinearities that map the output of the filters to the neuronal spike rates. We found that cells respond differently to these two classes of stimuli, with mostly higher spike rates and shorter response latencies to NSs than to WGN. The most striking finding was that NSs resulted in RFs that had additional uncovered filters compared with WGN. This finding was not an artifact of the higher spike rates observed for NSs relative to WGN, but rather was related to a change in coding. Our results reveal a greater extent of nonlinear processing in V1 neurons when stimulated using NSs compared with WGN. Our findings ind...

The posterior parietal cortex (PPC) plays a key role in integrating sensory inputs from different modalities to support adaptive behavior. Neuronal activity in PPC reflects perceptual decision-making across behavioral tasks, but the mechanistic involvement of PPC is unclear. In an audiovisual change detection task, we tested the hypothesis that PPC is required to arbitrate between the noisy inputs from the two different modalities and help decide in which modality a sensory change occurred. In trained male mice, we found extensive single-neuron and population-level encoding of task-relevant visual and auditory stimuli, trial history, as well as upcoming behavioral responses. However, despite these rich neural correlates, which would theoretically be sufficient to solve the task, optogenetic inactivation of PPC did not affect visual or auditory performance. Thus, despite neural correlates faithfully tracking sensory variables and predicting behavioral responses, PPC was not relevant for audiovisual change d...

Photoreceptor degeneration leads to irreversible vision loss in humans with retinal dystrophies such as retinitis pigmentosa. Whereas photoreceptor loss is permanent in mammals, zebrafish possesses the ability to regenerate retinal neurons and restore visual function. Following acute damage, Müller glia (MG) re-enter the cell cycle and produce multipotent progenitors whose progeny differentiate into mature neurons. Both MG reprogramming and proliferation of retinal progenitor cells require reactive microglia and associated inflammatory signaling. Paradoxically, in zebrafish models of retinal degeneration, photoreceptor death does not induce the MG to reprogram and regenerate lost cells. Here, we used male and female zebrafish cep290 mutants to demonstrate that progressive cone degeneration generates an immune response but does not stimulate MG proliferation. Acute light damage triggered photoreceptor regeneration in cep290 mutants but cones were only restored to prelesion densities. Using irf8 mutant zebra...

Hippocampal place cells form a map of the environment of an animal. Changes in the hippocampal map can be brought about in a number of ways, including changes to the environment, task, internal state of the subject, and the passage of time. These changes in the hippocampal map have been called remapping. In this study, we examine remapping during repeated exposure to the same environment. Different animals can have different remapping responses to the same changes. This variability across animals in remapping behavior is not well understood. In this work, we analyzed electrophysiological recordings from the CA3 region of the hippocampus performed by [Alme et al. (2014)][1], in which five male rats were exposed to 11 different environments, including a variety of repetitions of those environments. To compare the hippocampal maps between two experiences, we computed average rate map correlation coefficients. We found changes in the hippocampal maps between different sessions in the same environment. These ch...

The brain areas that mediate the formation of auditory threat memory and perceptual decisions remain uncertain to date. Candidates include the primary (A1) and secondary (A2) auditory cortex, the medial division of the medial geniculate body (MGm), amygdala, and the temporal association cortex. We used chemogenetic and optogenetic manipulations with in vivo and in vitro patch-clamp recordings to assess the roles of these brain regions in threat memory learning in female mice. We found that conditioned sound (CS) frequency-dependent plasticity resulted in the formation of auditory threat memory in the temporal association cortex. This neural correlated auditory threat memory depended on CS frequency information from A1 glutamatergic subthreshold monosynaptic inputs, CS lateral inhibition from A2 glutamatergic disynaptic inputs, and non–frequency-specific facilitation from MGm glutamatergic monosynaptic inputs. These results indicate that the A2 and MGm work together in an inhibitory-facilitative role. SIGN...