Coordinated head direction representations in mouse anterodorsal thalamic nucleus and retrosplenial cortex.

The sense of direction is critical for survival in changing environments and relies on flexibly integrating self-motion signals with external sensory cues. While the anatomical substrates involved in head direction (HD) coding are well known, the mechanisms by which visual information updates HD representations remain poorly understood. Retrosplenial cortex (RSC) plays a key role in forming coherent representations of space in mammals and it encodes a variety of navigational variables, including HD. Here, we use simultaneous two-area tetrode recording to show that RSC HD representation is nearly synchronous with that of the anterodorsal nucleus of thalamus (ADn), the obligatory thalamic relay of HD to cortex, during rotation of a prominent visual cue. Moreover, coordination of HD representations in the two regions is maintained during darkness. We further show that anatomical and functional connectivity are consistent with a strong feedforward drive of HD information from ADn to RSC, with anatomically restricted corticothalamic feedback. Together, our results indicate a concerted global HD reference update across cortex and thalamus.

Vectorized instructive signals in cortical dendrites during a brain-computer interface task.

Backpropagation of error is the most widely used learning algorithm in artificial neural networks, forming the backbone of modern machine learning and artificial intelligence1,2. Backpropagation provides a solution to the credit assignment problem by vectorizing an error signal tailored to individual neurons. Recent theoretical models have suggested that neural circuits could implement backpropagation-like learning by semi-independently processing feedforward and feedback information streams in separate dendritic compartments3-7. This presents a compelling, but untested, hypothesis for how cortical circuits could solve credit assignment in the brain. We designed a neurofeedback brain-computer interface (BCI) task with an experimenter-defined reward function to evaluate the key requirements for dendrites to implement backpropagation-like learning. We trained mice to modulate the activity of two spatially intermingled populations (4 or 5 neurons each) of layer 5 pyramidal neurons in the retrosplenial cortex to rotate a visual grating towards a target orientation while we recorded GCaMP activity from somas and corresponding distal apical dendrites. We observed that the relative magnitudes of somatic versus dendritic signals could be predicted using the activity of the surrounding network and contained information about task-related variables that could serve as instructive signals, including reward and error. The signs of these putative teaching signals both depended on the causal role of individual neurons in the task and predicted changes in overall activity over the course of learning. These results provide the first biological evidence of a backpropagation-like solution to the credit assignment problem in the brain.

A unified open-source platform for multimodal neural recording and perturbation during naturalistic behavior.

Behavioral neuroscience faces two conflicting demands: long-duration recordings from large neural populations and unimpeded animal behavior. To meet this challenge, we developed ONIX, an open-source data acquisition system with high data throughput (2GB/sec) and low closed-loop latencies (<1ms) that uses a novel 0.3 mm thin tether to minimize behavioral impact. Head position and rotation are tracked in 3D and used to drive active commutation without torque measurements. ONIX can acquire from combinations of passive electrodes, Neuropixels probes, head-mounted microscopes, cameras, 3D-trackers, and other data sources. We used ONIX to perform uninterrupted, long (~7 hours) neural recordings in mice as they traversed complex 3-dimensional terrain. ONIX allowed exploration with similar mobility as non-implanted animals, in contrast to conventional tethered systems which restricted movement. By combining long recordings with full mobility, our technology will enable new progress on questions that require high-quality neural recordings during ethologically grounded behaviors.

Patch2MAP combines patch-clamp electrophysiology with super-resolution structural and protein imaging in identified single neurons without genetic modification.

Recent developments in super-resolution microscopy have revolutionized the study of cell biology. However, dense tissues require exogenous protein expression for single cell morphological contrast. In the nervous system, many cell types and species of interest - particularly human - are not amenable to genetic modification and/or exhibit intricate anatomical specializations which make cellular delineation challenging. Here, we present a method for full morphological labeling of individual neurons from any species or cell type for subsequent cell-resolved protein analysis without genetic modification. Our method, which combines patch-clamp electrophysiology with epitope-preserving magnified analysis of proteome (eMAP), further allows for correlation of physiological properties with subcellular protein expression. We applied Patch2MAP to individual spiny synapses in human cortical pyramidal neurons and demonstrated that electrophysiological AMPA-to-NMDA receptor ratios correspond tightly to respective protein expression levels. Patch2MAP thus permits combined subcellular functional, anatomical, and proteomic analyses of any cell, opening new avenues for direct molecular investigation of the human brain in health and disease.

Highly synchronized cortical circuit dynamics mediate spontaneous pain in mice.

Cortical neural dynamics mediate information processing for the cerebral cortex, which is implicated in fundamental biological processes such as vision and olfaction, in addition to neurological and psychiatric diseases. Spontaneous pain is a key feature of human neuropathic pain. Whether spontaneous pain pushes the cortical network into an aberrant state and, if so, whether it can be brought back to a "normal" operating range to ameliorate pain are unknown. Using a clinically relevant mouse model of neuropathic pain with spontaneous pain-like behavior, we report that orofacial spontaneous pain activated a specific area within the primary somatosensory cortex (S1), displaying synchronized neural dynamics revealed by intravital two-photon calcium imaging. This synchronization was underpinned by local GABAergic interneuron hypoactivity. Pain-induced cortical synchronization could be attenuated by manipulating local S1 networks or clinically effective pain therapies. Specifically, both chemogenetic inhibition of pain-related c-Fos-expressing neurons and selective activation of GABAergic interneurons significantly attenuated S1 synchronization. Clinically effective pain therapies including carbamazepine and nerve root decompression could also dampen S1 synchronization. More important, restoring a "normal" range of neural dynamics through attenuation of pain-induced S1 synchronization alleviated pain-like behavior. These results suggest that spontaneous pain pushed the S1 regional network into a synchronized state, whereas reversal of this synchronization alleviated pain.

Filopodia are a structural substrate for silent synapses in adult neocortex.

Newly generated excitatory synapses in the mammalian cortex lack sufficient AMPA-type glutamate receptors to mediate neurotransmission, resulting in functionally silent synapses that require activity-dependent plasticity to mature. Silent synapses are abundant in early development, during which they mediate circuit formation and refinement, but they are thought to be scarce in adulthood1. However, adults retain a capacity for neural plasticity and flexible learning that suggests that the formation of new connections is still prevalent. Here we used super-resolution protein imaging to visualize synaptic proteins at 2,234 synapses from layer 5 pyramidal neurons in the primary visual cortex of adult mice. Unexpectedly, about 25% of these synapses lack AMPA receptors. These putative silent synapses were located at the tips of thin dendritic protrusions, known as filopodia, which were more abundant by an order of magnitude than previously believed (comprising about 30% of all dendritic protrusions). Physiological experiments revealed that filopodia do indeed lack AMPA-receptor-mediated transmission, but they exhibit NMDA-receptor-mediated synaptic transmission. We further showed that functionally silent synapses on filopodia can be unsilenced through Hebbian plasticity, recruiting new active connections into a neuron's input matrix. These results challenge the model that functional connectivity is largely fixed in the adult cortex and demonstrate a new mechanism for flexible control of synaptic wiring that expands the learning capabilities of the mature brain.

Differential dendritic integration of long-range inputs in association cortex via subcellular changes in synaptic AMPA-to-NMDA receptor ratio.

Synaptic NMDA receptors can produce powerful dendritic supralinearities that expand the computational repertoire of single neurons and their respective circuits. This form of supralinearity may represent a general principle for synaptic integration in thin dendrites. However, individual cortical neurons receive many diverse classes of input that may require distinct postsynaptic decoding schemes. Here, we show that sensory, motor, and thalamic inputs preferentially target basal, apical oblique, and distal tuft dendrites, respectively, in layer 5b pyramidal neurons of the mouse retrosplenial cortex, a visuospatial association area. These dendritic compartments exhibited differential expression of NMDA receptor-mediated supralinearity due to systematic changes in the AMPA-to-NMDA receptor ratio. Our results reveal a new schema for integration in cortical pyramidal neurons, in which dendrite-specific changes in synaptic receptors support input-localized decoding. This coexistence of multiple modes of dendritic integration in single neurons has important implications for synaptic plasticity and cortical computation.

Rethinking Single Neuron Electrical Compartmentalization: Dendritic Contributions to Network Computation In Vivo.

Decades of experimental and theoretical work support a now well-established theory that active dendritic processing contributes to the computational power of individual neurons. This theory is based on the high degree of electrical compartmentalization observed in the dendrites of single neurons in ex vivo preparations. Compartmentalization allows dendrites to conduct semi-independent operations on their inputs before final integration and output at the axon, producing a "network-in-a-neuron." However, recent in vivo functional imaging experiments in mouse cortex have reported surprisingly little evidence for strong dendritic compartmentalization. In this review, we contextualize these new findings and discuss their impact on the future of the field. Specifically, we consider how highly coordinated, and thus less compartmentalized, activity in soma and dendrites can contribute to cortical computations including nonlinear mixed selectivity, prediction/expectation, multiplexing, and credit assignment.

A Randomized Phase 1 Evaluation of Deupirfenidone, a Novel Deuterium-Containing Drug Candidate for Interstitial Lung Disease and Other Inflammatory and Fibrotic Diseases.

LYT-100 (deupirfenidone) is a selectively deuterated form of pirfenidone under development for the treatment of inflammatory and fibrotic diseases, including interstitial lung disease. Adverse events associated with antifibrotics can be a barrier to adoption and persistence in patients with interstitial lung diseases, most of whom are not on standard-of-care therapy. LYT-100 is designed to have a differentiated pharmacokinetic (PK) profile from pirfenidone and could offer a differentiated safety profile compared to current standard-of-care drugs while retaining the biochemical potency and specificity of pirfenidone. We conducted a phase 1b study to ascertain the safety, tolerability, steady-state PK profile, and food effect of LYT-100. This was a 2-part study. Part 1 assessed multiple ascending doses of LYT-100 from 100, 250, 500, 750, and 1000 mg twice daily given over 5 days without titration. Part 2 assessed the effects of fed vs fasting conditions on the PK profile of a single 500-mg dose of LYT-100. All doses up to 1000 mg were well tolerated, with adverse events being mild and transient. Exposure was slightly lower in the fed condition. LYT-100 was well tolerated and has a dose-proportional PK profile. The ratio of parent to major metabolite concentration was higher than reported with pirfenidone, which is consistent with an effect of deuteration on metabolism. No maximum tolerated dose was identified up to 1000 mg twice-daily dosing. These results support further clinical development of LYT-100, particularly considering the adverse event profile of current standard-of-care drugs.

Allometric rules for mammalian cortical layer 5 neuron biophysics.

The biophysical properties of neurons are the foundation for computation in the brain. Neuronal size is a key determinant of single neuron input-output features and varies substantially across species1-3. However, it is unknown whether different species adapt neuronal properties to conserve how single neurons process information4-7. Here we characterize layer 5 cortical pyramidal neurons across 10 mammalian species to identify the allometric relationships that govern how neuronal biophysics change with cell size. In 9 of the 10 species, we observe conserved rules that control the conductance of voltage-gated potassium and HCN channels. Species with larger neurons, and therefore a decreased surface-to-volume ratio, exhibit higher membrane ionic conductances. This relationship produces a conserved conductance per unit brain volume. These size-dependent rules result in large but predictable changes in somatic and dendritic integrative properties. Human neurons do not follow these allometric relationships, exhibiting much lower voltage-gated potassium and HCN conductances. Together, our results in layer 5 neurons identify conserved evolutionary principles for neuronal biophysics in mammals as well as notable features of the human cortex.

An international, randomized, placebo-controlled, phase 2b clinical trial of intepirdine for dementia with Lewy bodies (HEADWAY-DLB).

INTRODUCTION: A phase 2b clinical trial, HEADWAY-DLB, was performed to assess treatment with intepirdine, a serotonin receptor antagonist, in patients with dementia with Lewy bodies (DLB). METHODS: HEADWAY-DLB was a multinational, double-blind, randomized, placebo-controlled study. Two hundred sixty-nine DLB patients were randomized to receive placebo, 70 mg/day intepirdine, or 35 mg/day intepirdine over 24 weeks. The primary endpoint was change from baseline to week 24 on the Unified Parkinson's Disease Rating Scale-Part III (UPDRS-III). RESULTS: Both intepirdine groups did not demonstrate significant benefits over placebo at 24 weeks on the UPDRS-III (35 mg/day: P = .1580, 70 mg/day: P = .6069). All other endpoints were not significant. Intepirdine was well tolerated, with a slightly higher incidence of gastrointestinal adverse events observed in the intepirdine groups versus placebo. DISCUSSION: Intepirdine treatment did not lead to improvements over placebo in patients with DLB. As one of the largest DLB studies to date, HEADWAY-DLB demonstrates that international trials for DLB are feasible within a reasonable timeframe.

Intepirdine as adjunctive therapy to donepezil for mild-to-moderate Alzheimer's disease: A randomized, placebo-controlled, phase 3 clinical trial (MINDSET).

INTRODUCTION: A previous phase 2b study supported the use of the 5-HT6 receptor antagonist intepirdine as adjunctive therapy to donepezil for Alzheimer's disease (AD) dementia. A phase 3 study, MINDSET, was performed to test this hypothesis. METHODS: MINDSET was a global, double-blind, randomized, placebo-controlled trial in 1315 mild-to-moderate AD dementia patients on stable donepezil. Patients received 35 mg/day intepirdine or placebo for 24 weeks. The co-primary endpoints were change from baseline to week 24 on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL). RESULTS: There were no statistically significant differences between intepirdine and placebo groups (adjusted mean [95% confidence interval]) on the co-primary endpoints ADAS-Cog (-0.36 [-0.95, 0.22], P = 0.2249) and ADCS-ADL (-0.09 [-0.90, 0.72], P = 0.8260). Intepirdine demonstrated a favorable safety profile similar to placebo. DISCUSSION: Intepirdine as adjunctive therapy to donepezil did not produce statistical improvement over placebo on cognition or activities of daily living in mild-to-moderate AD dementia patients.

Inhibition of phosphodiesterase-4D in adults with fragile X syndrome: a randomized, placebo-controlled, phase 2 clinical trial.

The goal of this study was to determine whether a phosphodiesterase-4D (PDE4D) allosteric inhibitor (BPN14770) would improve cognitive function and behavioral outcomes in patients with fragile X syndrome (FXS). This phase 2 trial was a 24-week randomized, placebo-controlled, two-way crossover study in 30 adult male patients (age 18-41 years) with FXS. Participants received oral doses of BPN14770 25 mg twice daily or placebo. Primary outcomes were prespecified as safety and tolerability with secondary efficacy outcomes of cognitive performance, caregiver rating scales and physician rating scales (ClinicalTrials.gov identifier: NCT03569631 ). The study met the primary outcome measure since BPN14770 was well tolerated with no meaningful differences between the active and placebo treatment arms. The study also met key secondary efficacy measures of cognition and daily function. Cognitive benefit was demonstrated using the National Institutes of Health Toolbox Cognition Battery assessments of Oral Reading Recognition (least squares mean difference +2.81, P = 0.0157), Picture Vocabulary (+5.81, P = 0.0342) and Cognition Crystallized Composite score (+5.31, P = 0.0018). Benefit as assessed by visual analog caregiver rating scales was judged to be clinically meaningful for language (+14.04, P = 0.0051) and daily functioning (+14.53, P = 0.0017). Results from this study using direct, computer-based assessment of cognitive performance by adult males with FXS indicate significant cognitive improvement in domains related to language with corresponding improvement in caregiver scales rating language and daily functioning.

IV tramadol: A novel option for US patients with acute pain-A review of its pharmacokinetics, abuse potential and clinical safety record.

Tramadol is a centrally acting dual-mechanism (opioid and monoamine reuptake inhibition) analgesic that has been noted to have a lower risk of abuse compared to conventional opioids such as morphine. Oral tramadol has been ap-proved in the United States since 1995 and intravenous (IV) tramadol has been widely prescribed outside the United States (OUS); nevertheless, IV tramadol has not yet been approved for use in the United States. This paper provides a review of the pharmacokinetics (PK) of the IV tramadol dosing regimen being developed in the United States, its abuse potential as documented in the literature, and its safety record in clinical practice, and discusses how IV tramadol may become a useful option for patients in the United States with acute pain.

Efficacy and Safety of Intravenously Administered Tramadol in Patients with Moderate to Severe Pain Following Bunionectomy: A Randomized, Double-Blind, Placebo-Controlled, Dose-Finding Study.

INTRODUCTION: This study is part of the registrational program for intravenously administered (IV) tramadol in the USA and compared the analgesic benefit and tolerability of two doses of IV tramadol (50 mg and 25 mg) to placebo in adult patients undergoing bunionectomy, an orthopedic surgical model. METHODS: This was a phase 3, multicenter, double-blind, three-arm, randomized, placebo-controlled, multiple-dose, parallel-group trial to evaluate IV tramadol in the management of postoperative pain following bunionectomy. Eligible patients were randomized (1:1:1 ratio) to IV tramadol 50 mg, 25 mg, or placebo. Primary endpoint was summary of pain intensity differences over 48 h (SPID48). Key secondary endpoints included SPID24, total consumption of rescue analgesia, and patient global assessment of efficacy (PGA). Safety assessments included treatment emergent adverse events (TEAEs), clinical laboratory tests, vital signs, and electrocardiograms (ECGs). Assessment of the dose-response was an important objective of the study. RESULTS: The study established a dose response, with IV tramadol 50 mg demonstrating statistically significant benefit (p < 0.05) over placebo for primary and all key secondary efficacy endpoints, whereas tramadol 25 mg demonstrated intermediate results between the 50 mg and placebo arms. IV tramadol 50 mg was well tolerated; most common TEAEs were nausea and vomiting; and there were no meaningful differences among treatments for vital signs, ECG, and laboratory assessments. The largest proportion of patients completed tramadol 50 mg (98.6%) compared to tramadol 25 mg (91.8%) and placebo (88.2%). CONCLUSION: IV tramadol 50 mg was effective and well tolerated as treatment for postoperative pain following bunionectomy surgery, while IV tramadol 25 mg, although well tolerated, was judged an ineffective dose for the treatment of pain in this setting. IV tramadol 50 mg was further developed in the registrational program for the USA. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03290378.

Misuse of Tramadol in the United States: An Analysis of the National Survey of Drug Use and Health 2002-2017.

OBJECTIVE: To analyze the rates of misuse - that is, use in any way not directed by a doctor - of products containing oral tramadol, a Schedule IV opioid, from the National Survey of Drug Use and Health (NSDUH), as compared to comparator Schedule II opioids (morphine, oxycodone, and hydrocodone) and alprazolam, a commonly prescribed Schedule IV controlled substance in the U.S. METHODS: The NSDUH is a congressionally mandated household survey that collects information on tobacco, alcohol, and drug use, mental health and other health-related issues in the US. A cross-sectional surveillance study design was used to examine lifetime and past year misuse of oral tramadol and comparators of interest among NSHUH respondents aged 12 years or older. Based on when particular data were available, the past-year misuse analysis includes NSDUH data from 2015 to 2017, and the lifetime misuse analysis includes NSDUH data from 2002 to 2014. RESULTS: In 2015 to 2017, past-year misuse of oral tramadol was approximately 4% of the total number of prescriptions, versus 7% to 8% for all of the comparators when adjusted for drug availability. In 2002 to 2014, lifetime misuse of oral tramadol remained at 1.5% or less over the 13-year period, and was lower than reported for hydrocodone (6%) and oxycodone (4%), respectively. Comparison of oral tramadol and alprazolam showed misuse of tramadol was also much lower than alprazolam. Too few reports of tramadol misuse by injection (n = 7) were reported, versus 570, 1096, and 32 reports of injection of morphine, oxycodone, and hydrocodone, respectively, during the 16-year analysis period to allow for any population-based estimation. Only morphine has an intravenous formulation available and tramadol was not available as an intravenous formulation in the U.S. during that time period. CONCLUSIONS: This analysis shows a low prevalence of oral tramadol misuse, relative to other commonly prescribed opioids, in a nationally representative sample of noninstitutionalized US residents. Estimates of reported oral tramadol misuse have remained relatively stable over time and are substantially lower than those reported for comparators when adjusted for prescription volume. Reports of oral tramadol misuse are also much less than alprazolam, another Schedule IV drug.

IV Tramadol - A New Treatment Option for Management of Post-Operative Pain in the US: An Open-Label, Single-Arm, Safety Trial Including Various Types of Surgery.

PURPOSE: There is a need to reduce exposure to Schedule II opioids in the United States (US) due to the ongoing opioid epidemic. Schedule II opioids have higher potential for abuse and misuse than Schedule IV opioids. This Phase 3, multicenter, single-arm, open-label, multiple-dose US trial evaluated the safety and tolerability of intravenous tramadol 50 mg, a Schedule IV opioid, in the management of postoperative pain in a real-world setting, where intravenous tramadol is not yet approved for use. PATIENTS AND METHODS: Patients undergoing a range of soft-tissue and orthopedic surgeries were enrolled. Intravenous tramadol 50 mg was given at hours 0, 2, 4, and every 4 h thereafter through up to 7 days of treatment. Non-opioid medications per treating physicians' discretion were allowed if additional pain relief was needed. Endpoints included treatment-emergent adverse events (TEAEs), laboratories, vital signs, electrocardiograms (ECGs), and patient global assessment (PGA) of effectiveness. RESULTS: A total of 251 patients were enrolled, with 4% discontinuing due to TEAE; no patient discontinued due to a lack of efficacy. Patients averaged 13 doses, resulting in average 48 h of exposure. Intravenous tramadol was well tolerated, with TEAEs consistent with known tramadol pharmacology. No unexpected findings were observed, with 95% of patients reporting study medication was good, very good, or excellent for controlling pain. CONCLUSION: Outcomes from this real world use study demonstrated intravenous tramadol 50 mg was safe and well tolerated in the management of postoperative pain where intravenous conventional opioids are often used. Intravenous tramadol alone or coadministered with non-opioid medication (when needed) as a multimodal combination analgesia approach resulted in high patient satisfaction with their pain relief. In light of the US opioid epidemic, reducing the exposure to conventional opioids in these patients via use of IV tramadol may be possible.

Intravenous Tramadol is Effective in the Management of Postoperative Pain Following Abdominoplasty: A Three-Arm Randomized Placebo- and Active-Controlled Trial.

BACKGROUND AND OBJECTIVE: Oral tramadol, an atypical opioid approved in the United States (US) since 1995 and a Schedule IV controlled substance, has less abuse liability compared to Schedule II conventional opioids. Intravenous (IV) tramadol is not available in the US, but has the potential to fill a gap between non-opioid medications and conventional opioids for treatment of acute pain. This study evaluates IV tramadol in the management of postoperative pain compared to placebo and standard-of-care active control. METHODS: A phase 3, multicenter, double-blind, three-arm, randomized, placebo- and active-controlled, multiple-dose, parallel-group study was conducted to evaluate the efficacy and safety of 50 mg IV tramadol versus placebo and 4 mg IV morphine over 48 h in patients with postoperative pain following abdominoplasty surgery. RESULTS: IV tramadol was statistically superior (p < 0.05) to placebo and comparable to IV morphine for the primary and all key secondary efficacy outcomes and demonstrated numerically lower rates for the incidence of most common treatment-emergent adverse events (TEAEs) compared to morphine. No unexpected findings were observed for TEAEs, laboratory tests, vital signs, or electrocardiograms (ECGs). Over 90% of patients completed the study. CONCLUSION: The study demonstrated that IV tramadol 50 mg is highly effective in the management of postoperative pain following abdominoplasty. The consistency of effects between tramadol and morphine (as compared to placebo) for primary and key secondary endpoints validates the efficacy of tramadol observed. The study also provided direct evidence of improved tolerability of IV tramadol over a standard-of-care conventional Schedule II opioid. IV tramadol may become a useful option in patients where exposure to conventional opioids is not desired.

Representation of visual landmarks in retrosplenial cortex.

The process by which visual information is incorporated into the brain's spatial framework to represent landmarks is poorly understood. Studies in humans and rodents suggest that retrosplenial cortex (RSC) plays a key role in these computations. We developed an RSC-dependent behavioral task in which head-fixed mice learned the spatial relationship between visual landmark cues and hidden reward locations. Two-photon imaging revealed that these cues served as dominant reference points for most task-active neurons and anchored the spatial code in RSC. This encoding was more robust after task acquisition. Decoupling the virtual environment from mouse behavior degraded spatial representations and provided evidence that supralinear integration of visual and motor inputs contributes to landmark encoding. V1 axons recorded in RSC were less modulated by task engagement but showed surprisingly similar spatial tuning. Our data indicate that landmark representations in RSC are the result of local integration of visual, motor, and spatial information.

When moving through a city, people often use notable or familiar landmarks to help them navigate. Landmarks provide us with information about where we are and where we need to go next. But despite the ease with which we ­ and most other animals ­ use landmarks to find our way around, it remains unclear exactly how the brain makes this possible. One area that seems to have a key role is the retrosplenial cortex, which is located deep within the back of the brain in humans. This area becomes more active when animals use visual landmarks to navigate. It is also one of the first brain regions to be affected in Alzheimer's disease, which may help to explain why patients with this condition can become lost and disoriented, even in places they have been many times before. To find out how the retrosplenial cortex supports navigation, Fischer et al. measured its activity in mice exploring a virtual reality world. The mice ran through simulated corridors in which visual landmarks indicated where hidden rewards could be found. The activity of most neurons in the retrosplenial cortex was most strongly influenced by the mouse's position relative to the landmark; for example, some neurons were always active 10 centimeters after the landmark. In other experiments, when the landmarks were present but no longer indicated the location of a reward, the same neurons were much less active. Fischer et al. also measured the activity of the neurons when the mice were running with nothing shown on the virtual reality, and when they saw a landmark but did not run. Notably, the activity seen when the mice were using the landmarks to find rewards was greater than the sum of that recorded when the mice were just running or just seeing the landmark without a reward, making the "landmark response" an example of so-called supralinear processing. Fischer et al. showed that visual centers of the brain send information about landmarks to retrosplenial cortex. But only the latter adjusts its activity depending on whether the mouse is using that landmark to navigate. These findings provide the first evidence for a "landmark code" at the level of neurons and lay the foundations for studying impaired navigation in patients with Alzheimer's disease. By showing that retrosplenial cortex neurons combine different types of input in a supralinear fashion, the results also point to general principles for how neurons in the brain perform complex calculations.

An easy-to-assemble, robust, and lightweight drive implant for chronic tetrode recordings in freely moving animals.

Tetrode arrays are a standard method for neuronal recordings in behaving animals, especially for chronic recordings of many neurons in freely-moving animals. OBJECTIVE: We sought to simplify tetrode drive designs with the aim of enabling building and implanting a 16-tetrode drive in a single day. APPROACH: Our design makes use of recently developed technologies to reduce the complexity of the drive while maintaining a low weight. MAIN RESULTS: The design presents an improvement over existing implants in terms of robustness, weight, and ease of use. We describe two variants: a 16 tetrode implant weighing ∼2 g for mice, bats, tree shrews and similar animals, and a 64 tetrode implant weighing ∼16 g for rats and similar animals. These designs were co-developed and optimized alongside a new class of drive-mounted feature-rich amplifier boards with ultra-thin radio-frequency tethers, as described in an upcoming paper (Newman, Zhang et al in prep). SIGNIFICANCE: This design significantly improves the data yield of chronic electrophysiology experiments.