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Frankland, P. W.

Publications and source records attributed to Frankland, P. W..

17 recordsLinked to original sources

Delayed maturation of hippocampal trisynaptic circuitry underlies the protracted development of episodic-like memory

The ability to form high-resolution episodic memories emerges relatively late in development, but the circuit mechanisms underlying this transition are unknown. CA1 receives entorhinal input through a direct monosynaptic pathway and an indirect trisynaptic pathway via the dentate gyrus and CA3. In mice, CA3[->]CA1 innervation matured later than MEC[->]CA1 innervation, with pronounced maturation between P20 and P24. Trisynaptic pathway maturation was necessary for high-resolution memory and was shaped by neuronal activity and early-life experience. Mechanistically, trisynaptic activity promoted perineuronal net assembly around downstream parvalbumin-expressing interneurons, facilitating their maturation and subsequent recruitment during learning to constrain CA1 encoding ensembles. Thus, activity-dependent maturation of trisynaptic circuitry provides a unified circuit and cellular account of a sensitive period for the emergence of episodic-like memory.

neuroscience↗

Activity-dependent myelination in prefrontal circuits signals the offset of infantile amnesia

Human and non-human infants can form memories for events, but these memories are not successfully consolidated into remote memory. While the neurobiological basis of this phenomenon-known as infantile amnesia-remains unclear, it is hypothesized that the neural circuits required for successful consolidation are insufficiently mature. Here we find that heightened activity in the prelimbic cortex of developing mice triggers a sequalae of maturational steps that culminates in adult-like memory persistence: Activity-dependent increases in brain-derived neurotrophic factor (BDNF) promote myelination of prelimbic circuits via activation of tyrosine kinase receptor B (TrkB) receptors on oligodendrocyte precursor cells (OPCs). Inhibiting any of these steps within a critical developmental window delays the offset of infantile amnesia, whereas promoting this sequalae results in the precocial emergence of memory persistence. Similar to critical periods in sensory cortices, our results indicate that developmental myelination is required for proper circuit maturation and emergence of adult-like memory function.

neuroscience↗

Whole-brain analyses identify anterior cingulate μ-opioid signaling as a critical mediator of placebo analgesia in neuropathic pain

Placebo analgesia reflects the capacity of learning and expectation to engage endogenous pain-control systems, yet the neural circuits that support this phenomenon remain poorly understood. Here, we establish a conditioning-based placebo analgesia paradigm in mice following peripheral nerve injury and combine behavioral assessment with whole-brain activity mapping and targeted circuit manipulations to define its neural substrates. Conditioning with morphine produced robust placebo analgesia, expressed as reduced sensory sensitivity in the absence of drug. Brain-wide mapping of c-Fos expression revealed distributed changes across cortical and subcortical regions accompanied by a reorganization of functional connectivity, consistent with coordinated network-level engagement. Network analyses identified shifts in hub structure and selective strengthening and weakening of inter-regional interactions during placebo analgesia. Causal manipulations demonstrated a critical role for the anterior cingulate cortex, with excitatory activation of this region blocking placebo analgesia, whereas inhibitory manipulations had no effect. In contrast, perturbation of other candidate regions, including the basomedial amygdala and paraventricular thalamus, did not alter placebo responses. Finally, selective targeting of -opioid receptor-expressing neurons in the anterior cingulate cortex revealed that this cell population is necessary for the expression of placebo analgesia. Together, these findings reveal a brain-wide reorganization of network interactions underlying placebo analgesia and identify a specific cortical opioid circuit that gates its expression. One-Sentence SummaryUsing a mouse model of nerve injury, this study shows that placebo analgesia arises from coordinated brain-wide network reorganization and is gated by -opioid receptor-expressing neurons in the anterior cingulate cortex.

neuroscience↗

Interventionally targeting somatic CAG expansions can be a rapid disease-modifying therapeutic avenue: Preclinical evidence.

Huntington disease (HD) is caused by inherited CAG expansions, which continue expanding somatically in affected brain regions to hasten disease onset and progression. Therapeutically diminishing somatic expansions is expected to be clinically beneficial. However, it is not known if interventionally modifying somatic CAG expansions will actually modify in vivo clinically-relevant phenotypes, what the therapeutic window is, or which phenotypes will be altered. Here we show that acute (6-week) delivery of the contraction-inducing slipped-CAG DNA ligand naphthyridine-azaquinolone to young (4-week-old) (CAG)120 HD mice, induces contractions throughout brain regions, improves motor function (locomotion, balance, coordination, muscle strength), molecular disease landmarks (mHTT aggregates, nuclear envelope morphology, nucleocytoplasmic mRNA transport, transcriptomic dysregulation, neuroinflammation), and neurodegeneration. Beneficial effects of modifying somatic expansions were also evident in muscle and blood, where blood CAG instability correlated with brain instability and blood serum had diminished levels of neurofilament light (a biomarker for neurodegeneration) -- offering blood as having elements of target engagement and efficacy. These data support that targeting somatic repeat expansions can be a rapid disease-modifying therapeutic avenue for HD and possibly other repeat expansion diseases. Our findings support an etiologic pathway interconnected to somatic CAG expansions that will inform the design of clinical trials expecting clinical benefit by modulating somatic expansions.

genetics↗

A sensitive period for the development of episodic-like memory in mice

Episodic-like memory is a later-developing cognitive function supported by the hippocampus. In mice, the formation of extracellular perineuronal nets in subfield CA1 of the dorsal hippocampus controls the emergence of episodic-like memory during the fourth postnatal week (Ramsaran et al., 2023). Whether the timing of episodic-like memory onset is hard-wired, or flexibly set by early-life experiences during a critical or sensitive period for hippocampal maturation, is unknown. Here, we show that the trajectories for episodic-like memory development vary for mice given different sets of experiences spanning the second and third postnatal weeks. Specifically, episodic-like memory precision developed later in mice that experienced early-life adversity, while it developed earlier in mice that experienced early-life enrichment. Moreover, we demonstrate that early-life experiences set the timing of episodic-like memory development by modulating the pace of perineuronal net formation in dorsal CA1. These results indicate that the hippocampus undergoes a sensitive period during which early-life experiences determine the timing for episodic-like memory development.

neuroscience↗

Single cell approaches define forebrain neural stem cell niches and identify microglial ligands that enhance precursor-mediated remyelination

Here we used single cell RNA-sequencing and single cell spatial transcriptomics to characterize the forebrain neural stem cell (NSC) niche under homeostatic and injury conditions. We define the dorsal and lateral ventricular-subventricular zones (V-SVZ) as two distinct neighborhoods, and show that following white matter injury, dorsal NSCs are locally activated to make oligodendrocytes for remyelination. This activation is coincident with a robust increase in transcriptionally-distinct microglia in the dorsal V-SVZ niche. We modeled ligand-receptor interactions within this changing niche and identified two remyelination-associated microglial ligands, IGF1 and OSM, that promote precursor proliferation and oligodendrogenesis in culture. Infusion of either ligand into the lateral ventricles also enhanced oligodendrogenesis, even in the lateral V-SVZ, where NSCs normally make neuroblasts. These data support a model where gliogenesis versus neurogenesis is determined by the local NSC neighborhood and where injury-induced niche alterations promote NSC activation, local oligodendrogenesis, and likely contribute to myelin repair.

neuroscience↗

A shift in the mechanisms controlling hippocampal engram formation during brain maturation

The ability to form precise, episodic memories develops with age, with young children only able to form gist-like memories that lack precision. The cellular and molecular events in the developing hippocampus that underlie the emergence of precise, episodic-like memory formation are unclear. In mice, the absence of a competitive neuronal engram allocation process in the immature hippocampus precluded the formation of sparse engrams and precise memories until the fourth postnatal week, when inhibitory circuits in the hippocampus mature. This age-dependent shift in precision of episodic-like memories involved the functional maturation of parvalbumin-expressing interneurons in subfield CA1 by extracellular perineuronal nets which is necessary and sufficient for the onset of competitive neuronal allocation, sparse engram formation, and memory precision. One-Sentence SummaryEpisodic-like memory precision requires maturation of hippocampal inhibitory interneurons by the extracellular matrix.

neuroscience↗

Evolution of predictive memory in the hippocampus

The brain organizes experiences into memories that can be used to guide future behavior. Hippocampal CA1 population activity may reflect the retrieval of predictive models that contain information about future events, but little is known about how these kinds of memories develop with experience. We trained mice on a series of tone discrimination problems with or without a common statistical structure to observe how memories are formed and updated during learning. Mice that learned structured problems integrated their experiences into a predictive model that contained the solutions to upcoming novel problems. Retrieving the model during learning improved discrimination accuracy and facilitated learning by decreasing the amount of new information that needed to be acquired. Using calcium imaging to track the activity of thousands of CA1 neurons during learning on this task, we observed the emergence of a persistent hippocampal ensemble at the same time that mice formed a predictive model of their environment. This ensemble was reactivated during training and incorporated new neuronal activity patterns from each training problem. Interestingly, the degree to which mice reactivated the ensemble was related to how well their model predicted the content of the current problem, ensuring that the model was only updated with congruent information. In contrast, mice trained on unstructured problems did not form a predictive model or engage a persistent ensemble. These results show how hippocampal activity supports building predictive models by organizing newly learned information according to its congruence with existing memories.

neuroscience↗

Can neurogenesis act as a neural regularizer?

New neurons are continuously generated in the subgranular zone of the dentate gyrus throughout adulthood. These new neurons gradually integrate into hippocampal circuits, forming new naive synapses. Viewed from this perspective, these new neurons may represent a significant source of wiring noise in hippocampal networks. In machine learning, such noise injection is commonly used as a regularization technique. Regularization techniques help prevent overfitting training data, and allow models to generalize learning to new, unseen data. Using a computational modeling approach, here we ask whether a neurogenesis-like process similarly acts as a regularizer, facilitating generalization in a category learning task. In a convolutional neural network (CNN) trained on the CIFAR-10 object recognition dataset, we modeled neurogenesis as a replacement/turnover mechanism, where weights for a randomly chosen small subset of neurons in a chosen hidden layer were re-initialized to new values as the model learned to categorize 10 different classes of objects. We found that neurogenesis enhanced generalization on unseen test data compared to networks with no neurogenesis. Moreover, neurogenic networks either outperformed or performed similarly to networks with conventional noise injection (i.e., dropout, weight decay, and neural noise). These results suggest that neurogenesis can enhance generalization in hippocampal learning through noise-injection, expanding on the roles that neurogenesis may have in cognition. Author SummaryIn deep neural networks, various forms of noise injection are used as regularization techniques to prevent overfitting and promote generalization on unseen test data. Here, we were interested in whether adult neurogenesis- the lifelong production of new neurons in the hippocampus- might similarly function as a regularizer in the brain. We explored this question computationally, assessing whether implementing a neurogenesis-like process in a hidden layer within a convolutional neural network trained in a category learning task would prevent overfitting and promote generalization. We found that neurogenesis regularization was as least as effective as, or more effective than, conventional regularizers (i.e., dropout, weight decay and neural noise) in improving model performance. These results suggest that optimal levels of hippocampal neurogenesis may improve memory-guided decision making by preventing overfitting, thereby promoting the formation of more generalized memories that can be applied in a broader range of circumstances. We outline how these predictions may be evaluated behaviorally in rodents with altered hippocampal neurogenesis.

neuroscience↗

Why do hippocampal mossy cells matter? It depends on the frequency and context.

The discrimination of similar episodes and places, and their representation as distinct memories, depend on a process called pattern separation that relies on the circuitry of the hippocampal dentate gyrus (DG). Mossy cells (MCs) are key neurons in the circuitry, but how they influence DG network dynamics, function, and seizure risk has not been fully elucidated. We found the net impact of MCs was inhibitory at physiological frequencies connected with learning and behaviour, and their absence associated with deficits in pattern separation and spatial memory; at higher frequencies, their net impact was excitatory, and their absence protected against seizures. Thus, MCs influence DG outputs in a highly dynamic manner that varies with frequency and context. One-Sentence SummaryHippocampal mossy cells are required for learning and memory; but their absence protects against seizures.

neuroscience↗

Toxoplasma infection alters dopamine-sensitive behaviors and host gene expression patterns associated with neuropsychiatric disease

Toxoplasma gondii is a single celled parasite thought to infect 1 in 3 worldwide. During chronic infection, T. gondii can migrate to the brain where it promotes low-grade neuroinflammation with the capacity to induce changes in brain morphology and behavior. Consequently, infection with T. gondii has been linked with a number of neurocognitive disorders including schizophrenia (SZ), dementia, and Parkinsons disease. Beyond neuroinflammation, infection with T. gondii can modulate the production of neurotransmitters, such as dopamine. To further dissect these pathways and examine the impact of altered dopaminergic sensitivity in T. gondii-infected mice on both behavior and gene expression, we developed a novel mouse model, based on stimulant-induced (cocaine) hyperactivity. Employing this model, we found that infection with T. gondii did not alter fear behavior but did impact motor activity and neuropsychiatric-related behaviurs. While both behaviors may help reduce predator avoidance, consistent with previous studies, the latter finding is reminiscent of neurocognitive disorders. Applying RNASeq to two relevant brain regions, striatum and hippocampus, we identified a broad upregulation of immune responses. However, we also noted significant associations with more meaningful neurologically relevant terms were masked due to the sheer number of terms incorporated in multiple testing correction. We therefore performed a more focused analysis using a curated set of neurologically relevant terms revealing significant associations across multiple pathways. We also found that T. gondii and cocaine treatments impacted the expression of similar functional pathways in the hippocampus and striatum although, as indicated by the low overlap among differentially expressed genes, largely via different proteins. Furthermore, while most differentially expressed genes reacted to a single condition and were mostly upregulated, we identified gene expression patterns indicating unexpected interactions between T. gondii infection and cocaine exposure. These include sets of genes which responded to cocaine exposure but not upon cocaine exposure in the context of T. gondii infection, suggestive of a neuroprotective effect advantageous to parasite persistence. Given its ability to uncover such complex relationships, we propose this novel model offers a new perspective to dissect the molecular pathways by which T. gondii infection contributes to neuropsychiatric disorders such as schizophrenia.

microbiology↗

AZBA: A 3D Adult Zebrafish Brain Atlas for the Digital Age

Zebrafish have made significant contributions to our understanding of the vertebrate brain and the neural basis of behavior, earning a place as one of the most widely used model organisms in neuroscience. Their appeal arises from the marriage of low cost, early life transparency, and ease of genetic manipulation with a behavioral repertoire that becomes more sophisticated as animals transition from larvae to adults. To further enhance the use of adult zebrafish, we created the first fully segmented three-dimensional digital adult zebrafish brain atlas (AZBA). AZBA was built by combining tissue clearing, light-sheet fluorescence microscopy, and three-dimensional image registration of nuclear and antibody stains. These images were used to guide segmentation of the atlas into over 200 neuroanatomical regions comprising the entirety of the adult zebrafish brain. As an open source, online azba.wayne.edu), updatable digital resource, AZBA will significantly enhance the use of adult zebrafish in furthering our understanding of vertebrate brain function in both health and disease.

neuroscience↗

Neurogenesis-mediated forgetting of complex paired-associates memories

The hippocampus is a critical structure involved in many forms of learning and memory. It is also one of the only regions in the adult mammalian brain that continues to generate new neurons throughout adulthood. This process of adult neurogenesis may increase the plasticity of the hippocampus which could be beneficial for learning but has also been demonstrated to decrease the stability of previously acquired memories. Here we test whether increased production of new neurons following the formation of a gradually acquired paired-associates task will result in forgetting of this type of memory. We trained mice in a touchscreen-based object/location task and then increased neurogenesis using voluntary exercise. Our results indicate that mice with increased neurogenesis show poor recall of the previously established memory. When subsequently exposed to a reversal task we also show that mice with increased neurogenesis require fewer correction trials to acquire the new task contingencies. This suggests that prior forgetting reduces perseveration on the now outdated memory. Together our results add to a growing body of literature which indicates the important role of adult neurogenesis in destabilizing previously acquired memories to allow for flexible encoding of new memories.

animal behavior and cognition↗

Changes in the functional connectome and behavior after exposure to chronic stress and increasing neurogenesis

Addition of new neurons to the dentate gyrus might change the activity of neural circuitry in the areas which the hippocampus projects to. The size of the hippocampus and the number of adult newborn granule cells are decreased by unpredictable chronic mild stress (UCMS). Additionally, one of the notable effects of chronic stress is the induction of {Delta}FosB, an unusually stable transcription factor which accumulates over time in several brain areas. This accumulation has been observed in many animal models of depression and it could have a protective role against stress, but no studies so far have explored how a specific increase in neurogenesis might regulate the induction and which brain networks might be predominately affected. We attempted to investigate the role of increasing adult hippocampal neurogenesis on stress-related behavior and the functional brain circuitry involved in mice exposed to UCMS. We used iBax mice, in which the pro-apoptotic gene Bax can be selectively ablated in neural stem cells, therefore inducibly enhancing survival of newborn neurons after tamoxifen administration. The animals were exposed to UCMS for 9 weeks and treated with tamoxifen in week 3 after the beginning of UCMS. In week 8, they were submitted to a battery of behavioral tests to assess depressive-like and anxiety-like behavior. In week 9, blood was collected to assess basal corticosterone levels, and the animals were sacrificed and their brain collected for {Delta}FosB immunohistochemistry. Brain-wide maps of {Delta}FosB expression were constructed and graph theoretical analyses were used to study the changes in brain networks after stress. UCMS induced negative correlations between the lateral entorhinal cortex and both the hippocampal structures and the nucleus accumbens in the VEH-treated mice, which were not present in other groups. Ranking nodes by degree reveals a strong thalamic-cortical signature in both non-stress (NS) groups. Exposure to UCMS seems to induce activity in thalamic areas and cerebral nuclei, with a different signature in the UCMS TAM group, which seems to completely "disengage" the neocortex and has most of its nodes with the most connections in the thalamic areas.

neuroscience↗

Automated curation of CNMF-E-extracted ROI spatial footprints and calcium traces using open-source AutoML tools

In vivo 1-photon calcium imaging is an increasingly prevalent method in behavioural neuroscience. Numerous analysis pipelines have been developed to improve the reliability and scalability of pre-processing and ROI extraction for these large calcium imaging datasets. Despite these advancements in pre-processing methods, manual curation of the extracted spatial footprints and calcium traces of neurons remains important for quality control. Here, we propose an additional semi-automated curation step for sorting spatial footprints and calcium traces from putative neurons extracted using the popular CNMF-E algorithm. We used the automated machine learning tools TPOT and AutoSklearn to generate classifiers to curate the extracted ROIs trained on a subset of human-labeled data. AutoSklearn produced the best performing classifier, achieving an F1 score > 92% on the ground truth test dataset. This automated approach is a useful strategy for filtering ROIs with relatively few labeled data points, and can be easily added to pre-existing pipelines currently using CNMF-E for ROI extraction.

neuroscience↗

A compact head-mounted endoscope for in vivo calcium imaging in freely-behaving mice

Miniaturized fluorescence microscopes for imaging calcium transients are a promising tool for investigating the relationship between behaviour and population-level neuronal activity in rodents. However, commercially available miniature microscopes may be costly, and, because they are closed-source, may not be easily modified based on particular experimental requirements. Here, we describe how to build and use a low-cost compact head-mounted endoscope (CHEndoscope) system for in vivo calcium imaging. The CHEndoscope uses an implanted gradient index (GRIN) lens along with the genetically encoded calcium indicator GCaMP6 to image calcium transients from hundreds of neurons simultaneously in awake behaving mice. This system is affordable, open-source, and flexible, permitting modification depending on the particular experiment. This Unit describes in detail the assembly, surgical implantation, data collection, and processing of calcium signals using the CHEndoscope system. The aim of this open framework model is to provide an accessible set of miniaturized calcium imaging tools for the neuroscience research community.\n\nSignificance StatementThe ability to image calcium transients in awake, behaving rodents using miniature microscopes opens exciting and novel avenues for gaining insights into how information is encoded in neural circuits. The development of this tool has already had a significant impact on neuroscience research. The cost of commercial systems, however, may be prohibitive for many laboratories. Here, we describe an affordable, open-source compact head-mounted endoscope (CHEndoscope) system for performing in vivo calcium imaging in freely-behaving mice. CHEndoscopes may be manufactured by individual laboratories at relatively minor cost. Our hope is that greater availability of affordable, open-source tools (such as the one presented here) will accelerate the pace of discoveries in systems neuroscience.

neuroscience↗

Running Promotes Spatial Bias Independently Of Adult Neurogenesis

Different memory systems offer distinct advantages to navigational behavior. The hippocampus forms complex associations between environmental stimuli, enabling flexible navigation through space. In contrast, the dorsal striatum associates discrete cues and favorable behavioral responses, enabling habit-like, automated navigation. While these two systems often complement one another, there are instances where striatal-dependent responses (e.g. approach a cue) conflict with hippocampal representations of spatial goals. In conflict situations, preference for spatial vs. response strategies varies across individuals and depends on previous experience, plasticity and the integrity of these two memory systems. Here, we investigated the role of adult hippocampal neurogenesis and exercise on mouse search strategies in a water maze task that can be solved with either a hippocampal-dependent place strategy or a striatal-dependent cue-response strategy. We predicted that inhibiting adult neurogenesis would impair hippocampal function and shift behavior towards striatal-dependent cue responses. However, blocking neurogenesis in a transgenic nestin-TK mouse did not affect strategy choice. We then investigated whether a pro-neurogenic stimulus, running, would bias mice towards hippocampal-dependent spatial strategies. While running indeed promoted spatial strategies, it did so even when neurogenesis was inhibited in nestin-TK mice. These findings indicate that exercise-induced increases in neurogenesis are not always required for enhanced cognitive function. Furthermore, our data identify exercise as a potentially useful strategy for promoting flexible, cognitive forms of memory in habit-related disorders that are characterized by excessive responding to discrete cues.

neuroscience↗