Inbred mice (C57Bl/6) display wide variability in performance on hippocampal-dependent cognitive tasks. Examination of micro-dissected dentate gyrus (DG) after cognitive testing showed a highly significant negative correlation between levels of bone morphometric protein (BMP) signaling and recognition memory. Cognitive performance decline during the aging process, and the degree of cognitive decline is strongly correlated with aging-related increases in BMP signaling. Further, cognitive performance was impaired when the BMP inhibitor, noggin, was knocked down in the DG. Infusion of noggin into the lateral ventricles enhanced DG-dependent cognition while BMP4 infusion led to significant impairments. Embryonic overexpression of noggin resulted in lifelong enhancement of recognition and spatial memory while overexpression of BMP4 resulted in lifelong impairment, substantiating the importance of differences in BMP signaling in wildtype mice. These findings indicate that performance in DG-dependent cognitive ta...

Wnt signaling is crucial for synapse and cognitive function. Indeed, deficient Wnt signaling is causally related to increased expression of DKK1, an endogenous negative Wnt regulator, and synapse loss, both of which likely contribute to cognitive decline in Alzheimer’s disease (AD). Increasingly, AD research efforts have probed the neuroinflammatory role of microglia, the resident immune cells of the CNS, which have furthermore been shown to be modulated by Wnt signaling. The DKK1 homolog DKK2 has been previously identified as an activated response and/or disease-associated microglia (DAM/ARM) gene in a mouse model of AD. Here, we performed a detailed analysis of DKK2 in mouse models of neurodegeneration, and in human AD brain. In APP/PS1 and APPNL-G-F AD mouse model brains as well as in SOD1G93A ALS mouse model spinal cords, but not in control littermates, we demonstrated significant microgliosis and microglial Dkk2 mRNA upregulation in a disease-stage-dependent manner. In the AD models, these DAM/ARM Dkk...

Midbrain dopaminergic (DAergic) neurons of the ventral tegmental area (VTA) are engaged by rewarding stimuli and encode reward prediction error to update goal-directed learning. However, recent data indicate VTA DAergic neurons are functionally heterogeneous with emerging roles in aversive signaling, salience, and novelty, based in part on anatomical location and projection, highlighting a need to functionally characterize the repertoire of VTA DAergic efferents in motivated behavior. Previous work identifying a mesointerpeduncular circuit consisting of VTA DAergic neurons projecting to the interpeduncular nucleus (IPN), a midbrain area implicated in aversion, anxiety-like behavior, and familiarity, has recently come into question. To verify the existence of this circuit, we combined presynaptic targeted and retrograde viral tracing in the dopamine transporter (DAT)-Cre mouse line. Consistent with previous reports, synaptic tracing revealed axon terminals from the VTA innervate the caudal IPN; whereas, ret...

When two sufficiently different stimuli are presented to each eye, perception alternates between them. This binocular rivalry is conceived as a competition for representation in the single stream of visual consciousness. The magnocellular (M) and parvocellular (P) pathways, originating in the retina, encode disparate information, but their potentially different contributions to binocular rivalry have not been determined. Here, we used functional magnetic resonance imaging to measure the human lateral geniculate nucleus (LGN), where the M and P neurons are segregated into layers receiving input from a single eye. We had three participants (one male, two females) and used achromatic stimuli to avoid contributions from color opponent neurons that may have confounded previous studies. We observed activity in the eye-specific regions of LGN correlated with perception, with similar magnitudes during rivalry or physical stimuli alternations, also similar in the M and P regions. These results suggest that LGN acti...

Environmental enrichment (EE) is beneficial for brain development and function, but our understanding of its capacity to drive circuit repair, the underlying mechanisms, and how this might vary with age remains limited. Ten-m3 knock-out (KO) mice exhibit a dramatic and stereotyped mistargeting of ipsilateral retinal inputs to the thalamus, resulting in visual deficits. We have recently shown a previously unexpected capacity for EE during early postnatal life (from birth for six weeks) to drive the partial elimination of miswired axonal projections, along with a recovery of visually mediated behavior, but the timeline of this repair was unclear. Here, we reveal that with just 3.5 weeks of EE from birth, Ten-m3 KOs exhibit a partial behavioral rescue, accompanied by pruning of the most profoundly miswired retinogeniculate terminals. Analysis suggests that the pruning is underway at this time point, providing an ideal opportunity to probe potential mechanisms. With the shorter EE-period, we found a localized ...

The noradrenergic locus coeruleus (LC) is among the earliest sites of tau and α-synuclein pathology in Alzheimer’s disease (AD) and Parkinson’s disease (PD), respectively. The onset of these pathologies coincides with loss of noradrenergic fibers in LC target regions and the emergence of prodromal symptoms including sleep disturbances and anxiety. Paradoxically, these prodromal symptoms are indicative of a noradrenergic hyperactivity phenotype, rather than the predicted loss of norepinephrine (NE) transmission following LC damage, suggesting the engagement of complex compensatory mechanisms. Because current therapeutic efforts are targeting early disease, interest in the LC has grown, and it is critical to identify the links between pathology and dysfunction. We employed the LC-specific neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), which preferentially damages LC axons, to model early changes in the LC-NE system pertinent to AD and PD in male and female mice. DSP-4 (two doses of 50 mg/kg...

Injuries to peripheral nerves are frequent, yet no drug therapies are available for effective nerve repair. The slow growth rate of axons and inadequate access to growth factors challenge natural repair of nerves. A better understanding of the molecules that can promote the rate of axon growth may reveal therapeutic opportunities. Molecular profiling of injured neurons at early intervals of injury, when regeneration is at the maximum, has been the gold standard for exploring growth promoters. A complementary in vitro regenerative priming model was recently shown to induce enhanced outgrowth in adult sensory neurons. In this work, we exploited the in vitro priming model to reveal novel candidates for adult nerve regeneration. We performed a whole-tissue proteomics analysis of the in vitro primed dorsal root ganglia (DRGs) from adult SD rats and compared their molecular profile with that of the in vivo primed, and control DRGs. The proteomics data generated are available via ProteomeXchange with identifier P...

Postsynaptic scaffolding proteins function as central organization hubs, ensuring the synaptic localization of neurotransmitter receptors, trans-synaptic adhesion proteins, and signaling molecules. Gephyrin is the major postsynaptic scaffolding protein at glycinergic and a subset of GABAergic inhibitory synapses. In contrast to cells outside the CNS, where one gephyrin isoform is predominantly expressed, neurons express different splice variants. In this study, we characterized the expression and scaffolding of neuronal gephyrin isoforms differing in the inclusion of the C4 cassettes located in the central C-domain. In hippocampal and cortical neuronal populations, gephyrin P1, lacking additional cassettes, is the most abundantly expressed isoform. In addition, alternative splicing generated isoforms carrying predominantly C4a, and minor amounts of C4c or C4d cassettes. We detected no striking difference in C4 isoform expression between different neuron types and a single neuron can likely express all C4 i...

Accurate and efficient quantification of animal behavior facilitates the understanding of the brain. An emerging approach within machine learning (ML) field is to combine multiple ML-based algorithms to quantify animal behavior. These so-called hybrid models have emerged because of limitations associated with supervised [e.g., random forest (RF)] and unsupervised [e.g., hidden Markov model (HMM)] ML models. For example, RF models lack temporal information across video frames, and HMM latent states are often difficult to interpret. We sought to develop a hybrid model, and did so in the context of a study of mouse risk assessment behavior. We used DeepLabCut to estimate the positions of mouse body parts. Positional features were calculated using DeepLabCut outputs and were used to train RF and HMM models with equal number of states, separately. The per-frame predictions from RF and HMM models were then passed to a second HMM model layer (“reHMM”). The outputs of the reHMM layer showed improved interpretabili...

Midbrain dopaminergic (DAergic) neurons of the ventral tegmental area (VTA) are engaged by rewarding stimuli and encode reward prediction error to update goal-directed learning. However, recent data indicate that VTA DAergic neurons are functionally heterogeneous with emerging roles in aversive signaling, salience, and novelty, based in part on anatomic location and projection, highlighting a need to functionally characterize the repertoire of VTA DAergic efferents in motivated behavior. Previous work identifying a mesointerpeduncular circuit consisting of VTA DAergic neurons projecting to the interpeduncular nucleus (IPN), a midbrain area implicated in aversion, anxiety-like behavior, and familiarity, has recently come into question. To verify the existence of this circuit, we combined presynaptic targeted and retrograde viral tracing in the dopamine transporter-Cre mouse line. Consistent with previous reports, synaptic tracing revealed that axon terminals from the VTA innervate the caudal IPN; whereas, r...