Whole-body knock-out of Cu,Zn superoxide dismutase (Sod1KO) results in accelerated, age-related loss of muscle mass and function associated with neuromuscular junction (NMJ) breakdown similar to sarcopenia. In order to determine whether altered redox in motor neurons underlies this phenotype, an inducible neuron-specific deletion of Sod1 (i-mnSod1KO) was compared with wild-type (WT) mice of different ages (adult, mid-age, and old) and whole-body Sod1KO mice. Nerve oxidative damage, motor neuron numbers and structural changes to neurons and NMJ were examined. Tamoxifen-induced deletion of neuronal Sod1 from two months of age. No specific effect of a lack of neuronal Sod1 was seen on markers of nerve oxidation (electron paramagnetic resonance of an in vivo spin probe, protein carbonyl, or protein 3-nitrotyrosine contents). i-mnSod1KO mice showed increased denervated NMJ, reduced numbers of large axons and increased number of small axons compared with old WT mice. A large proportion of the innervated NMJs in ...

Allopregnanolone (AlloP) is a neurosteroid that potentiates ionotropic GABAergic (GABAA) inhibition and is approved for treating postpartum depression in women. Although the antidepressant mechanism of AlloP is largely unknown, it could involve selective action at GABAA receptors containing the δ subunit. Despite previous evidence for selective effects of AlloP on α4/δ-containing receptors of hippocampal dentate granule cells (DGCs), other recent results failed to demonstrate selectivity at these receptors ([Lu et al., 2020][1]). In contrast to DGCs, hippocampal fast-spiking parvalbumin (PV) interneurons express an unusual variant partnership of δ subunits with α1 subunits. Here, we hypothesized that native α1/δ receptors in hippocampal fast-spiking interneurons may provide a preferred substrate for AlloP. Contrary to the hypothesis, electrophysiology from genetically tagged PV interneurons in hippocampal slices from male mice showed that 100 nm AlloP promoted phasic inhibition by increasing the sIPSC deca...

The hippocampal theta rhythm strongly correlates to awake behavior leading to theories that it represents a cognitive state of the brain. As theta has been observed in other regions of the Papez circuit, it has been theorized that activity propagates in a reentrant manner. These observations complement the energy cascade hypothesis in which large-amplitude, slow-frequency oscillations reflect activity propagating across a large population of neurons. Higher frequency oscillations, such as gamma, are related to the speed with which inhibitory and excitatory neurons interact and distribute activity on the local level. The energy cascade hypothesis suggests that the larger anatomical loops, maintaining theta, drive the smaller loops. As hippocampal theta increases in power with running speed, so does the power and frequency of the gamma rhythm. If theta is propagated through the circuit, it stands to reason that the local field potential recorded in other regions would be coupled to the hippocampal theta, wit...

State-of-the-art all-optical systems promise unprecedented access to neural activity in vivo , using multiphoton optogenetics to allow simultaneous imaging and control of activity in selected neurons at cellular resolution. However, to achieve wide use of all-optical stimulation and imaging, simple strategies are needed to robustly and stably express opsins and indicators in the same cells. Here we describe a bicistronic adeno-associated virus (AAV) that expresses both the fast and bright calcium indicator jGCaMP8s, and a soma-targeted (st) and two-photon-activatable opsin, ChrimsonR. With this method, stChrimsonR stimulation with two-photon holography in the visual cortex of mice drives robust spiking in targeted cells, and neural responses to visual sensory stimuli and spontaneous activity are strong and stable. Cells expressing this bicistronic construct show responses to both photostimulation and visual stimulation that are similar to responses measured from cells expressing the same opsin and indicato...

Autoimmune encephalitis (AIE) associated with antibodies directed against the leucine-rich glioma inactivated 1 (LGI1) protein is the second most common AIE and is responsible for deleterious neocortical and limbic epileptic seizures. Previous studies demonstrated a pathogenic role of anti-LGI1 antibodies via alterations in the expression and function of Kv1 channels and AMPA receptors. However, the causal link between antibodies and epileptic seizures has never been demonstrated. Here, we attempted to determine the role of human anti-LGI1 autoantibodies in the genesis of seizures by analyzing the impact of their intracerebral injection in rodents. Acute and chronic injections were performed in rats and mice in the hippocampus and primary motor cortex, the two main brain regions affected by the disease. Acute infusion of CSF or serum IgG of anti-LGI1 AIE patients did not lead to the emergence of epileptic activities, as assessed by multisite electrophysiological recordings over a 10 h period after injectio...

Rodent studies suggest that spike timing relative to hippocampal theta activity determines whether potentiation or depression of synapses arise. Such changes also depend on spike timing between presynaptic and postsynaptic neurons, known as spike timing-dependent plasticity (STDP). STDP, together with theta phase-dependent learning, has inspired several computational models of learning and memory. However, evidence to elucidate how these mechanisms directly link to human episodic memory is lacking. In a computational model, we modulate long-term potentiation (LTP) and long-term depression (LTD) of STDP, by opposing phases of a simulated theta rhythm. We fit parameters to a hippocampal cell culture study in which LTP and LTD were observed to occur in opposing phases of a theta rhythm. Further, we modulated two inputs by cosine waves with 0° and asynchronous phase offsets and replicate key findings in human episodic memory. Learning advantage was found for the in-phase condition, compared with the out-of-pha...

Relapse is a major problem in treating methamphetamine use disorder. “Incubation of craving” during abstinence is a rat model for persistence of vulnerability to craving and relapse. While methamphetamine incubation has previously been demonstrated in male and female rats, it has not been demonstrated after withdrawal periods greater than 51 d and most mechanistic work used males. Here, we address both gaps. First, although methamphetamine intake was higher in males during self-administration training (6 h/d × 10 d), incubation was similar in males and females, with “incubated” craving persisting through withdrawal day (WD)100. Second, using whole-cell patch-clamp recordings in medium spiny neurons (MSNs) of the nucleus accumbens (NAc) core, we assessed synaptic levels of calcium-permeable AMPA receptors (CP-AMPARs), as their elevation is required for expression of incubation in males. In both sexes, compared with saline-self-administering controls, CP-AMPAR levels were significantly higher in methamphetam...

Executive functions arise from multiple regions of the brain acting in concert. To facilitate such cross-regional computations, the brain is organized into distinct executive networks, like the frontoparietal network. Despite similar cognitive abilities across many domains, little is known about such executive networks in birds. Recent advances in avian fMRI have shown a possible subset of regions, including the nidopallium caudolaterale (NCL) and the lateral part of medial intermediate nidopallium (NIML), that may contribute to complex cognition, forming an action control system of pigeons. We investigated the neuronal activity of NCL and NIML. Single-cell recordings were obtained during the execution of a complex sequential motor task that required executive control to stop executing one behavior and continue with a different one. We compared the neuronal activity of NIML to NCL and found that both regions fully processed the ongoing sequential execution of the task. Differences arose from how behavioral...

Hippocampal pyramidal neurons (PNs) are traditionally conceptualized as homogeneous population. For the past few years, cumulating evidence has revealed the structural and functional heterogeneity of hippocampal pyramidal neurons. But the in vivo neuronal firing pattern of molecularly identified pyramidal neuron subclasses is still absent. In this study, we investigated the firing patterns of hippocampal PNs based on different expression profile of Calbindin (CB) during a spatial shuttle task in free moving male mice. We found that CB+ place cells can represent spatial information more efficiently than CB− place cells, albeit lower firing rates during running epochs. Furthermore, a subset of CB+ PNs shifted their theta firing phase during rapid-eye movement (REM) sleep states compared with running states. Although CB− PNs are more actively engaged in ripple oscillations, CB+ PNs showed stronger ripple modulation during slow-wave sleep (SWS). Our results pointed out the heterogeneity in neuronal representat...

Sign-tracking (ST) describes the propensity to approach and contact a Pavlovian reward cue. By contrast, goal-trackers (GTs) respond to such a cue by retrieving the reward. These behaviors index the presence of opponent cognitive-motivational traits, with STs exhibiting attentional control deficits, behavior dominated by incentive motivational processes, and vulnerability for addictive drug taking. Attentional control deficits in STs were previously attributed to attenuated cholinergic signaling, resulting from deficient translocation of intracellular choline transporters (CHTs) into synaptosomal plasma membrane. Here, we investigated a posttranslational modification of CHTs, poly-ubiquitination, and tested the hypothesis that elevated cytokine signaling in STs contributes to CHT modification. We demonstrated that intracellular CHTs, but not plasma membrane CHTs, are highly ubiquitinated in male and female sign-tracking rats when compared with GTs. Moreover, levels of cytokines measured in cortex and stria...