Recalibration of path integration in hippocampal place cells.

Hippocampal place cells are spatially tuned neurons that serve as elements of a 'cognitive map' in the mammalian brain1. To detect the animal's location, place cells are thought to rely upon two interacting mechanisms: sensing the position of the animal relative to familiar landmarks2,3 and measuring the distance and direction that the animal has travelled from previously occupied locations4-7. The latter mechanism-known as path integration-requires a finely tuned gain factor that relates the animal's self-movement to the updating of position on the internal cognitive map, as well as external landmarks to correct the positional error that accumulates8,9. Models of hippocampal place cells and entorhinal grid cells based on path integration treat the path-integration gain as a constant9-14, but behavioural evidence in humans suggests that the gain is modifiable15. Here we show, using physiological evidence from rat hippocampal place cells, that the path-integration gain is a highly plastic variable that can be altered by persistent conflict between self-motion cues and feedback from external landmarks. In an augmented-reality system, visual landmarks were moved in proportion to the movement of a rat on a circular track, creating continuous conflict with path integration. Sustained exposure to this cue conflict resulted in predictable and prolonged recalibration of the path-integration gain, as estimated from the place cells after the landmarks were turned off. We propose that this rapid plasticity keeps the positional update in register with the movement of the rat in the external world over behavioural timescales. These results also demonstrate that visual landmarks not only provide a signal to correct cumulative error in the path-integration system4,8,16-19, but also rapidly fine-tune the integration computation itself.

Whole-genome resequencing of the native sheep provides insights into the microevolution and identifies genes associated with reproduction traits.

BACKGROUND: Sheep genomes undergo numerous genes losses, gains and mutation that generates genome variability among breeds of the same species after long time natural and artificial selection. However, the microevolution of native sheep in northwest China remains elusive. Our aim was to compare the genomes and relevant reproductive traits of four sheep breeds from different climatic environments, to unveil the selection challenges that this species cope with, and the microevolutionary differences in sheep genomes. Here, we resequenced the genomes of 4 representative sheep breeds in northwest China, including Kazakh sheep and Duolang sheep of native breeds, and Hu sheep and Suffolk sheep of exotic breeds with different reproductive characteristics. RESULTS: We found that these four breeds had a similar expansion experience from ~ 10,000 to 1,000,000 years ago. In the past 10,000 years, the selection intensity of the four breeds was inconsistent, resulting in differences in reproductive traits. We explored the sheep variome and selection signatures by FST and θπ. The genomic regions containing genes associated with different reproductive traits that may be potential targets for breeding and selection were detected. Furthermore, non-synonymous mutations in a set of plausible candidate genes and significant differences in their allele frequency distributions across breeds with different reproductive characteristics were found. We identified PAK1, CYP19A1 and PER1 as a likely causal gene for seasonal reproduction in native sheep through qPCR, Western blot and ELISA analyses. Also, the haplotype frequencies of 3 tested gene regions related to reproduction were significantly different among four sheep breeds. CONCLUSIONS: Our results provide insights into the microevolution of native sheep and valuable genomic information for identifying genes associated with important reproductive traits in sheep.

Modulation of lateral septal and dorsomedial striatal neurons by hippocampal sharp-wave ripples, theta rhythm, and running speed.

Single units were recorded in hippocampus, lateral septum (LS), and dorsomedial striatum (DMS) while freely behaving rats (n = 3) ran trials in a T-maze task and rested in a holding bucket between trials. In LS, 28% (64/226) of recorded neurons were excited and 14% (31/226) were inhibited during sharp wave ripples (SWRs). LS neurons that were excited during SWRs fired preferentially on the downslope of hippocampal theta rhythm and had firing rates that were positively correlated with running speed; LS neurons that were inhibited during SWRs fired preferentially on the upslope of hippocampal theta rhythm and had firing rates that were negatively correlated with running speed. In DMS, only 3.3% (12/366) of recorded neurons were excited and 5.7% (21/366) were inhibited during SWRs. As in LS, DMS neurons that were excited by SWRs tended to have firing rates that were positively modulated by running speed, whereas DMS neurons that were inhibited by SWRs tended to have firing rates that were negatively modulated by running speed. But in contrast with LS, these two DMS subpopulations did not clearly segregate their spikes to different phases of the theta cycle. Based on these results and a review of prior findings, we discuss how concurrent activation of spatial trajectories in hippocampus and motor representations in LS and DMS may contribute to neural computations that support reinforcement learning and value-based decision making.

Polymorphisms and association of GRM1, GNAQ and HCRTR1 genes with seasonal reproduction and litter size in three sheep breeds.

Litter size is one of the important economic traits of livestock. Seasonal oestrus, ovulation and lambing of sheep have severely restricted the development of sheep farming in Xinjiang, China. The purpose of this study was to investigate the polymorphisms and genetic correlation between GRM1, GNAQ and HCRTR1 genes and the seasonal reproduction and litter size in three sheep breeds. The DNA mixed pool sequencing and PCR-SSCP methods were used to detect single nucleotide polymorphisms (SNPs) of GRM1, GNAQ and HCRTR1 genes in seasonal oestrous (Kazakh and Chinese Merino [Xinjiang Junken type]) and perennial oestrous (Hu) sheep breeds. The association between genetic polymorphism and litter size was also analysed. The results showed that T945C in exon 2 of GRM1 gene, C589T in exon 2 of HCRTR1 gene and A191G in exon 2 of GNAQ gene were identified by Sanger sequencing, and three genotypes were existed in each SNP site, which all belonged to the synonymous mutation. GRM1 (CC), GNAQ (GA) and HCRTR1 (TC) were the dominant genotypes of seasonal reproduction and litter size in Kazakh sheep and Chinese Merino sheep, respectively, while, in perennial oestrous Hu sheep populations, the dominant genotypes were GRM1 (TC), GNAQ (GA) and HCRTR1 (TC), respectively, and association analysis also confirmed the results. The above results implied that GRM1, GNAQ and HCRTR1 genes are significantly associated with lambing traits in Kazakh, Chinese Merino and Hu sheep. Among them, the locus of GRM1 (T945C), GNAQ (A191G) and HCRTR1 (C589T) might be considered as a potential molecular marker, which controls seasonal reproduction and litter size in sheep.

The Flagellar Transcriptional Regulator FtcR Controls Brucella melitensis 16M Biofilm Formation via a betI-Mediated Pathway in Response to Hyperosmotic Stress.

The expression of flagellar proteins in Brucella species likely evolved through genetic transference from other microorganisms, and contributed to virulence, adaptability, and biofilm formation. Despite significant progress in defining the molecular mechanisms behind flagellar gene expression, the genetic program controlling biofilm formation remains unclear. The flagellar transcriptional factor (FtcR) is a master regulator of the flagellar system's expression, and is critical for B. melitensis 16M's flagellar biogenesis and virulence. Here, we demonstrate that FtcR mediates biofilm formation under hyperosmotic stress. Chromatin immunoprecipitation with next-generation sequencing for FtcR and RNA sequencing of ftcR-mutant and wild-type strains revealed a core set of FtcR target genes. We identified a novel FtcR-binding site in the promoter region of the osmotic-stress-response regulator gene betI, which is important for the survival of B. melitensis 16M under hyperosmotic stress. Strikingly, this site autoregulates its expression to benefit biofilm bacteria's survival under hyperosmotic stress. Moreover, biofilm reduction in ftcR mutants is independent of the flagellar target gene fliF. Collectively, our study provides new insights into the extent and functionality of flagellar-related transcriptional networks in biofilm formation, and presents phenotypic and evolutionary adaptations that alter the regulation of B. melitensis 16M to confer increased tolerance to hyperosmotic stress.

Chemogenetic Modulation and Single-Photon Calcium Imaging in Anterior Cingulate Cortex Reveal a Mechanism for Effort-Based Decisions.

The ACC is implicated in effort exertion and choices based on effort cost, but it is still unclear how it mediates this cost-benefit evaluation. Here, male rats were trained to exert effort for a high-value reward (sucrose pellets) in a progressive ratio lever-pressing task. Trained rats were then tested in two conditions: a no-choice condition where lever-pressing for sucrose was the only available food option, and a choice condition where a low-value reward (lab chow) was freely available as an alternative to pressing for sucrose. Disruption of ACC, via either chemogenetic inhibition or excitation, reduced lever-pressing in the choice, but not in the no-choice, condition. We next looked for value coding cells in ACC during effortful behavior and reward consumption phases during choice and no-choice conditions. For this, we used in vivo miniaturized fluorescence microscopy to reliably track responses of the same cells and compare how ACC neurons respond during the same effortful behavior where there was a choice versus when there was no-choice. We found that lever-press and sucrose-evoked responses were significantly weaker during choice compared with no-choice sessions, which may have rendered them more susceptible to chemogenetic disruption. Together, findings from our interference experiments and neural recordings suggest that a mechanism by which ACC mediates effortful decisions is in the discrimination of the utility of available options. ACC regulates these choices by providing a stable population code for the relative value of different options.SIGNIFICANCE STATEMENT The ACC is implicated in effort-based decision-making. Here, we used chemogenetics and in vivo calcium imaging to explore its mechanism. Rats were trained to lever press for a high-value reward and tested in two conditions: a no-choice condition where lever-pressing for the high-value reward was the only option, and a choice condition where a low-value reward was also available. Inhibition or excitation of ACC reduced effort toward the high-value option, but only in the choice condition. Neural responses in ACC were weaker in the choice compared with the no-choice condition. A mechanism by which ACC regulates effortful decisions is in providing a stable population code for the discrimination of the utility of available options.

Long-Term Characterization of Hippocampal Remapping during Contextual Fear Acquisition and Extinction.

Hippocampal CA1 place cell spatial maps are known to alter their firing properties in response to contextual fear conditioning, a process called "remapping." In the present study, we use chronic calcium imaging to examine remapping during fear retrieval and extinction of an inhibitory avoidance task in mice of both sexes over an extended period of time and with thousands of neurons. We demonstrate that hippocampal ensembles encode space at a finer scale following fear memory acquisition. This effect is strongest near the shock grid. We also characterize the long-term effects of shock on place cell ensemble stability, demonstrating that shock delivery induces several days of high fear and low between-session place field stability, followed by a new, stable spatial representation that appears after fear extinction. Finally, we identify a novel group of CA1 neurons that robustly encode freeze behavior independently from spatial location. Thus, following fear acquisition, hippocampal CA1 place cells sharpen their spatial tuning and dynamically change spatial encoding stability throughout fear learning and extinction.SIGNIFICANCE STATEMENT The hippocampus contains place cells that encode an animal's location. This spatial code updates, or remaps, in response to environmental change. It is known that contextual fear can induce such remapping; in the present study, we use chronic calcium imaging to examine inhibitory avoidance-induced remapping over an extended period of time and with thousands of neurons and demonstrate that hippocampal ensembles encode space at a finer scale following electric shock, an effect which is enhanced by threat proximity. We also identify a novel group of freeze behavior-activated neurons. These results suggest that, more than merely shuffling their spatial code following threat exposure, place cells enhance their spatial coding with the possible benefit of improved threat localization.

An uncertainty principle for neural coding: Conjugate representations of position and velocity are mapped onto firing rates and co-firing rates of neural spike trains.

The hippocampal system contains neural populations that encode an animal's position and velocity as it navigates through space. Here, we show that such populations can embed two codes within their spike trains: a firing rate code ( R) conveyed by within-cell spike intervals, and a co-firing rate code ( R˙ ) conveyed by between-cell spike intervals. These two codes behave as conjugates of one another, obeying an analog of the uncertainty principle from physics: information conveyed in R comes at the expense of information in R˙ , and vice versa. An exception to this trade-off occurs when spike trains encode a pair of conjugate variables, such as position and velocity, which do not compete for capacity across R and R˙ . To illustrate this, we describe two biologically inspired methods for decoding R and R˙ , referred to as sigma and sigma-chi decoding, respectively. Simulations of head direction and grid cells show that if firing rates are tuned for position (but not velocity), then position is recovered by sigma decoding, whereas velocity is recovered by sigma-chi decoding. Conversely, simulations of oscillatory interference among theta-modulated "speed cells" show that if co-firing rates are tuned for position (but not velocity), then position is recovered by sigma-chi decoding, whereas velocity is recovered by sigma decoding. Between these two extremes, information about both variables can be distributed across both channels, and partially recovered by both decoders. These results suggest that populations with different spatial and temporal tuning properties-such as speed versus grid cells-might not encode different information, but rather, distribute similar information about position and velocity in different ways across R and R˙ . Such conjugate coding of position and velocity may influence how hippocampal populations are interconnected to form functional circuits, and how biological neurons integrate their inputs to decode information from firing rates and spike correlations.

Spatial synchronization codes from coupled rate-phase neurons.

During spatial navigation, the frequency and timing of spikes from spatial neurons including place cells in hippocampus and grid cells in medial entorhinal cortex are temporally organized by continuous theta oscillations (6-11 Hz). The theta rhythm is regulated by subcortical structures including the medial septum, but it is unclear how spatial information from place cells may reciprocally organize subcortical theta-rhythmic activity. Here we recorded single-unit spiking from a constellation of subcortical and hippocampal sites to study spatial modulation of rhythmic spike timing in rats freely exploring an open environment. Our analysis revealed a novel class of neurons that we termed 'phaser cells,' characterized by a symmetric coupling between firing rate and spike theta-phase. Phaser cells encoded space by assigning distinct phases to allocentric isocontour levels of each cell's spatial firing pattern. In our dataset, phaser cells were predominantly located in the lateral septum, but also the hippocampus, anteroventral thalamus, lateral hypothalamus, and nucleus accumbens. Unlike the unidirectional late-to-early phase precession of place cells, bidirectional phase modulation acted to return phaser cells to the same theta-phase along a given spatial isocontour, including cells that characteristically shifted to later phases at higher firing rates. Our dynamical models of intrinsic theta-bursting neurons demonstrated that experience-independent temporal coding mechanisms can qualitatively explain (1) the spatial rate-phase relationships of phaser cells and (2) the observed temporal segregation of phaser cells according to phase-shift direction. In open-field phaser cell simulations, competitive learning embedded phase-code entrainment maps into the weights of downstream targets, including path integration networks. Bayesian phase decoding revealed error correction capable of resetting path integration at subsecond timescales. Our findings suggest that phaser cells may instantiate a subcortical theta-rhythmic loop of spatial feedback. We outline a framework in which location-dependent synchrony reconciles internal idiothetic processes with the allothetic reference points of sensory experience.

Parenteral administration of l-arginine to twin-bearing Romney ewes during late pregnancy is associated with reduced milk somatic cell count during early lactation.

Maternal milk is the primary source of nutrition for suckling mammals, and its yield and composition are important determinants of survival during the early neonatal period. The objective of this study was to examine whether parenteral administration of l-Arg to twin-bearing ewes, during mid to late pregnancy, influenced prepartum maternal mammary gland development and subsequent lactation performance in the early postpartum period (14 d). At 80 d of pregnancy, multiparous Romney ewes were housed indoors in group pens, split into 2 cohorts, and fed a lucerne-based pellet diet, formulated to meet 100% of National Research Council-recommended requirements for twin-bearing pregnant ewes, once a day. Cohort 1 was administered l-Arg (72.7 mg/kg of live weight via i.v, 3 times a day) from d 100 of pregnancy until d 140. At d 140, ewes were euthanized and maternal mammary tissues were collected for analysis of the biochemical indices total DNA, RNA, protein, protein synthetic efficiency (protein:RNA), cell size (protein:DNA), transcriptional efficiency (RNA:DNA), and the abundance of mammalian target of rapamycin (mTOR) and mTORSer2448 protein. Cohort 2 was administered an identical l-Arg regimen as cohort 1, but from d 100 until parturition. Milk was collected over a 14-d period (d 1, 4, 7, 10, and 14) to assess milk yield and composition. In cohort 1, total mammary DNA (cell number) tended to be higher in l-Arg ewes, with no change in total mammary RNA or protein content, biochemical indices of protein synthetic efficiency, cell size or transcriptional efficiency, or mTOR protein abundance or phosphorylation. In cohort 2, milk composition analysis from l-Arg ewes showed lower (d 7-14) milk somatic cell counts, greater crude protein percentage from d 7 to 10 but lower at d 14, and altered absolute concentrations of some free AA (d 7 and 14) compared with controls. We propose that parenteral administration of l-Arg during late pregnancy is associated with increased mammary gland cellular content and decreased somatic cell counts during early lactation.

Effect of adding crude glycerine to diets with feed additives on the feed intake, ruminal degradability, volatile fatty acid concentrations and in vitro gas production of feedlot Nellore cattle.

The effects of adding crude glycerine with sodium monensin or essential oils to beef cattle diets on the intake, degradability of DM and nutrients, rumen concentration of volatile fatty acids (VFA) and in vitro gas production were evaluated. Five ruminally cannulated Nellore steers were randomly assigned to a 5 × 5 Latin square design. The treatments were as follows: CONT, without crude glycerine and additives; EO, with essential oils and without crude glycerine; MON, with sodium monensin and without crude glycerine; EOG, with essential oils and crude glycerine; MONG, with sodium monensin and crude glycerine. Treatments with essential oil and sodium monensin increased the NDF and STC intake and the DM degradability. When crude glycerine was combined with either sodium monensin or essential oil, there was a reduction in DM, NDF and STC intake and an increase in DM and CP degradability of the diets. The adding crude glycerine to essential oil diets reduced the CH4 production. Sodium monensin treatments reduced DM and NDF intake and the production of total gas, CH4 , total VFA and acetic acid concentration. In conclusion, the adding crude glycerine (200 g/kg DM) with either sodium monensin (0.03 g/kg DM) or essential oil (0.5 g/kg DM) can be utilized in diets for Nellore cattle without causing detrimental effects on feed intake and improving the DM degradability.

Effect of exogenous progesterone on embryo size and ewe uterine gene expression in an ovine 'dam size' model of maternal constraint.

Progesterone (P4), acting via its receptor, regulates uterine function and histotroph production, which are crucial to embryo growth. This study aimed to examine exogenous P4 effects on embryo size and differential endometrial gene expression at Day 19 of gestation using a 'dam size' sheep model of maternal constraint. Purebred Suffolk (S, genotypically large) embryos were transferred into recipient groups of Cheviot (C, genotypically small) or Suffolk ewes that had, or had not, been pre-treated with P4 from Days 0 to 6 of pregnancy. At Day 19S embryos were collected from four experimental groups: P4 pretreated S ewes (SP4; n=5), untreated S ewes (SnP4; n=15), P4 pretreated C ewes (CP4; n=7) and untreated C ewes (CnP4; n=21). Day-19 embryos from CP4 ewes were larger (P<0.05) than those from CnP4 ewes and similar in size (P>0.05) to embryos from SnP4 and SP4 ewes. Expression of mucin 1 (MUC1) and prostaglandin-endoperoxide synthase 2 (PTGS2) was upregulated in uterine horns ipsilateral to the corpus luteum from CP4 ewes. Prostaglandin receptor (PGR), MUC1 and PTGS2 expression was upregulated, whilst cathepsin L (CTSL) and radical S-adenosyl methionine domain-containing 2 (RSAD2) expression was downregulated in the ipsilateral horn of SP4 ewes. This suggests that pretreating ewes with exogenous P4 may alleviate early pregnancy maternal constraint via mechanisms that alter uterine function. However, further research is required to investigate the timing of P4 administration and its impact on conception rates.

Timing of exogenous progesterone administration is critical for embryo development and uterine gene expression in an ovine model of maternal constraint.

Progesterone (P4) administration in early pregnancy enhances embryo growth in sheep but is associated with decreased embryo survival. This study examined the effects of exogenous P4 administered during specific time periods between pregnancy Day 0 and Day 6 to determine the critical time point for advancement of embryo growth without pregnancy loss and to examine Day 6 and Day 19 endometrial gene expression. Suffolk (S) embryos were transferred into Cheviot (C) ewes that received exogenous P4 (CP4) on Days 0-3 (CP40-3), Days 0-6 (CP40-6), Days 2-4 (CP42-4) or Days 3-6 (CP43-6). Additionally, S embryos were transferred to C and S ewes that did not receive P4 (CnP4 and SnP4). Day 19 embryos from CP4 ewes were longer (P<0.05) than those from CnP4 ewes. CP42-4 ewes had embryos of similar size to those of CP40-3 and CP40-6 ewes but had higher pregnancy rates. There was altered expression of genes associated with embryo implantation and histotroph production: diacylglycerol-O-acyltransferase (DGAT2), hepatocyte growth factor (HGF) and prostaglandin endoperoxide synthase 2 (PTSG2) on Day 6 and endometrial galectin 15 (LGALS15) and mucin glycoprotein 1 (MUC1) on Day 19. This suggests that specific timing of P4 administration is critical to the enhanced embryo growth and survival observed. These findings provide a platform for further investigation aimed at advancing embryo development and survival.

Prefrontal infralimbic cortex mediates competition between excitation and inhibition of body movements during pavlovian fear conditioning.

The infralimbic subregion of the prefrontal cortex (IL) is broadly involved in behavioral flexibility, risk assessment, and outcome reinforcement. In aversive conditioning tasks, the IL has been implicated in fear extinction and in mediating transitions between Pavlovian and instrumental responses. Here we examine the role of the IL in mediating transitions between two competing Pavlovian fear responses, conditioned motor inhibition (CMI) and conditioned motor excitation (CME). Rats were trained to fear an auditory conditioned stimulus (CS) by pairing it with periorbital shock to one eyelid (the unconditioned stimulus [US]). Trained animals exhibited CMI responses (movement suppression) to the CS when they had not recently encountered the US (>24 hr), but, after recent encounters with the US (<5 min), the CS evoked CME responses (turning in circles away from anticipated shock). Animals then received bilateral infusions of muscimol or picrotoxin to inactivate or hyperactivate the IL, respectively. Neither drug reliably affected CMI responses, but there was a bidirectional effect on CME responses; inactivation of the IL attenuated CME responses, whereas hyperactivation potentiated CME responses. These results provide evidence that activation of the IL may promote behavioral strategies that involve mobilizing the body and suppress strategies that involve immobilizing the body. © 2016 Wiley Periodicals, Inc.

Functional development of the adult ovine mammary gland--insights from gene expression profiling.

BACKGROUND: The mammary gland is a dynamic organ that undergoes dramatic physiological adaptations during the transition from late pregnancy to lactation. Investigation of the molecular basis of mammary development and function will provide fundamental insights into tissue remodelling as well as a better understanding of milk production and mammary disease. This is important to livestock production systems and human health. Here we use RNA-seq to identify differences in gene expression in the ovine mammary gland between late pregnancy and lactation. RESULTS: Between late pregnancy (135 days of gestation ± 2.4 SD) and lactation (15 days post partum ± 1.27 SD) 13 % of genes in the sheep genome were differentially expressed in the ovine mammary gland. In late pregnancy, cell proliferation, beta-oxidation of fatty acids and translation were identified as key biological processes. During lactation, high levels of milk fat synthesis were mirrored by enrichment of genes associated with fatty acid biosynthesis, transport and lipogenesis. Protein processing in the endoplasmic reticulum was enriched during lactation, likely in support of active milk protein synthesis. Hormone and growth factor signalling and activation of signal transduction pathways, including the JAK-STAT and PPAR pathways, were also differently regulated, indicating key roles for these pathways in functional development of the ovine mammary gland. Changes in the expression of epigenetic regulators, particularly chromatin remodellers, indicate a possible role in coordinating the large-scale transcriptional changes that appear to be required to switch mammary processes from growth and development during late pregnancy to synthesis and secretion of milk during lactation. CONCLUSIONS: Coordinated transcriptional regulation of large numbers of genes is required to switch between mammary tissue establishment during late pregnancy, and activation and maintenance of milk production during lactation. Our findings indicate the remarkable plasticity of the mammary gland, and the coordinated regulation of multiple genes and pathways to begin milk production. Genes and pathways identified by the present study may be important for managing milk production and mammary development, and may inform studies of diseases affecting the mammary gland.

Distinct ensembles of medial prefrontal cortex neurons are activated by threatening stimuli that elicit excitation vs. inhibition of movement.

Neural circuits controlling defensive behavior were investigated by recording single units in medial prefrontal cortex (mPFC) and dorsolateral periaqueductal gray (dlPAG) while rats expressed conditioned fear responses to an auditory conditioned stimulus (CS; 20-s train of white noise pips) previously paired with an aversive unconditioned stimulus (US; 2-s train of periorbital shocks). The CS elicited conditioned movement inhibition (CMI; characterized by decreased movement speed and freezing) when rats had not recently encountered the US, whereas the CS elicited conditioned movement excitation (CME; characterized by increased movement speed and flight behavior) after recent US encounters. Many mPFC neurons were "strategy-selective" cells that changed their firing rates only when the CS elicited CME (15/71) or CMI (13/71) responses, whereas few mPFC cells (4/71) responded nonselectively to the CS during either response. By contrast, many dlPAG neurons (20/74) responded nonselectively to the CS, but most (40/74) were excited by the CS selectively during CME trials (and none during CMI trials). CME-selective neurons in dlPAG responded phasically after CS pips that elicited CME responses, whereas CME-selective neurons in mPFC showed tonically elevated activity before and after pips that evoked CME responses. These findings suggest that, at the time when the CS occurs, tonic firing rates of CME- and CMI-selective mPFC neurons may bias the rat's choice of whether to express CME vs. CMI responses, perhaps via projections to downstream structures (such as amygdala and PAG) that influence how sensory stimuli are mapped onto motor circuits that drive the expression of competing behaviors.

Correlated signatures of social behavior in cerebellum and anterior cingulate cortex.

The cerebellum has been implicated in the regulation of social behavior. Its influence is thought to arise from communication, via the thalamus, to forebrain regions integral in the expression of social interactions, including the anterior cingulate cortex (ACC). However, the signals encoded or the nature of the communication between the cerebellum and these brain regions is poorly understood. Here, we describe an approach that overcomes technical challenges in exploring the coordination of distant brain regions at high temporal and spatial resolution during social behavior. We developed the E-Scope, an electrophysiology-integrated miniature microscope, to synchronously measure extracellular electrical activity in the cerebellum along with calcium imaging of the ACC. This single coaxial cable device combined these data streams to provide a powerful tool to monitor the activity of distant brain regions in freely behaving animals. During social behavior, we recorded the spike timing of multiple single units in cerebellar right Crus I (RCrus I) Purkinje cells (PCs) or dentate nucleus (DN) neurons while synchronously imaging calcium transients in contralateral ACC neurons. We found that during social interactions a significant subpopulation of cerebellar PCs were robustly inhibited, while most modulated neurons in the DN were activated, and their activity was correlated with positively modulated ACC neurons. These distinctions largely disappeared when only non-social epochs were analyzed suggesting that cerebellar-cortical interactions were behaviorally specific. Our work provides new insights into the complexity of cerebellar activation and co-modulation of the ACC during social behavior and a valuable open-source tool for simultaneous, multimodal recordings in freely behaving mice.

Social behaviour is important for many animals, especially humans. It governs interactions between individuals and groups. One of the regions involved in social behaviour is the cerebellum, a part of the brain commonly known for controlling movement. It is likely that the cerebellum connects and influences other socially important areas in the brain, such as the anterior cingulate cortex. How exactly these regions communicate during social interaction is not well understood. One of the challenges studying communication between areas in the brain has been a lack of tools that can measure neural activity in multiple regions at once. To address this problem, Hur et al. developed a device called the E-Scope. The E-Scope can measure brain activity from two places in the brain at the same time. It can simultaneously record imaging and electrophysiological data of the different neurons. It is also small enough to be attached to animals without inhibiting their movements. Hur et al. tested the E-Scope by studying neurons in two regions of the cerebellum, called the right Crus I and the dentate nucleus, and in the anterior cingulate cortex during social interactions in mice. The E-Scope recorded from the animals as they interacted with other mice and compared them with those in mice that interacted with objects. During social interactions, Purkinje cells in the right Crus I were mostly less active, while neurons in the dentate nucleus and anterior cingulate cortex became overall more active. These results suggest that communication between the cerebellum and the anterior cingulate cortex is an important part of how the mouse brain coordinates social behaviour. The study of Hur et al. deepens our understanding of the function of the cerebellum in social behaviour. The E-Scope is an openly available tool to allow researchers to record communication between remote brain areas in small animals. This could be important to researchers trying to understand conditions like autism, which can involve difficulties in social interaction, or injuries to the cerebellum resulting in personality changes.

Optical activation of lateral amygdala pyramidal cells instructs associative fear learning.

Humans and animals can learn that specific sensory cues in the environment predict aversive events through a form of associative learning termed fear conditioning. This learning occurs when the sensory cues are paired with an aversive event occurring in close temporal proximity. Activation of lateral amygdala (LA) pyramidal neurons by aversive stimuli is thought to drive the formation of these associative fear memories; yet, there have been no direct tests of this hypothesis. Here we demonstrate that viral-targeted, tissue-specific expression of the light-activated channelrhodopsin (ChR2) in LA pyramidal cells permitted optical control of LA neuronal activity. Using this approach we then paired an auditory sensory cue with optical stimulation of LA pyramidal neurons instead of an aversive stimulus. Subsequently presentation of the tone alone produced behavioral fear responses. These results demonstrate in vivo optogenetic control of LA neurons and provide compelling support for the idea that fear learning is instructed by aversive stimulus-induced activation of LA pyramidal cells.

Genomic Regions Associated with Wool, Growth and Reproduction Traits in Uruguayan Merino Sheep.

The aim of this study was to identify genomic regions and genes associated with the fiber diameter (FD), clean fleece weight (CFW), live weight (LW), body condition score (BCS), pregnancy rate (PR) and lambing potential (LP) of Uruguayan Merino sheep. Phenotypic records of approximately 2000 mixed-age ewes were obtained from a Merino nucleus flock. Genome-wide association studies were performed utilizing single-step Bayesian analysis. For wool traits, a total of 35 genomic windows surpassed the significance threshold (PVE ≥ 0.25%). The proportion of the total additive genetic variance explained by those windows was 4.85 and 9.06% for FD and CFW, respectively. There were 42 windows significantly associated with LWM, which collectively explained 43.2% of the additive genetic variance. For BCS, 22 relevant windows accounted for more than 40% of the additive genetic variance, whereas for the reproduction traits, 53 genomic windows (24 and 29 for PR and LP, respectively) reached the suggestive threshold of 0.25% of the PVE. Within the top 10 windows for each trait, we identified several genes showing potential associations with the wool (e.g., IGF-1, TGFB2R, PRKCA), live weight (e.g., CAST, LAP3, MED28, HERC6), body condition score (e.g., CDH10, TMC2, SIRPA, CPXM1) or reproduction traits (e.g., ADCY1, LEPR, GHR, LPAR2) of the mixed-age ewes.

Genetic and phenotypic relationships between ewe reproductive performance and wool and growth traits in Uruguayan Ultrafine Merino sheep.

This study reports genetic parameters for yearling and adult wool and growth traits, and ewe reproductive performance. Data were sourced from an Uruguayan Merino flock involved in a long-term selection program focused on reduced fiber diameter (FD), and increased clean fleece weight (CFW) and live weight (LW). Pedigree and performance data from approximately 5,700 mixed-sex yearling lambs and 2,000 mixed-age ewes born between 1999 and 2019 were analyzed. The number of records ranged from 1,267 to 5,738 for yearling traits, and from 1,931 to 7,079 for ewe productive and reproductive performance. Data on yearling and adult wool traits, LW and body condition score (BCS), yearling eye muscle area (Y_EMA), and fat thickness (Y_FAT), and several reproduction traits were analyzed. The genetic relationships between FD and reproduction traits were not different from zero. Moderate unfavorable genetic correlations were found between adult CFW and ewe lifetime reproduction traits (-0.34 ±â€…0.08 and -0.33 ±â€…0.09 for the total number of lambs weaned and total lamb LW at weaning, respectively). There were moderate to strong positive genetic correlations between yearling LW and all reproduction traits other than ewe-rearing ability (-0.08 ±â€…0.11) and pregnancy rate (0.18 ±â€…0.08). The genetic correlations between Y_EMA and reproduction traits were positive and ranged from 0.15 to 0.49. Moderate unfavorable genetic correlations were observed between yearling FD and Y_FAT and between adult FD and BCS at mating (0.31 ±â€…0.12 and 0.23 ±â€…0.07, respectively). The genetic correlations between adult fleece weight and ewe BCS at different stages of the cycle were negative, but generally not different from zero. This study shows that selection for reduced FD is unlikely to have any effect on reproduction traits. Selection for increased yearling LW and Y_EMA will improve ewe reproductive performance. On the other hand, selection for increased adult CFW will reduce ewe reproductive performance, whereas selection for reduced FD will negatively impact body fat levels. Although unfavorable genetic relationships between wool traits and both FAT and ewe reproductive performance existed, simultaneous improvements in the traits would occur using appropriately designed indexes.

Fiber diameter (FD), clean fleece weight (CFW), live weight (LW), and reproductive performance are important traits in Merino flocks. This study estimated the genetic parameters for a range of production traits and ewe reproductive performance. Data from approximately 5,700 mixed-sex yearling lambs and 2,000 mixed-age ewes born in a single Uruguayan Merino flock were analyzed. There were generally favorable (positive) genetic correlations between LW and reproduction traits. The genetic relationships between FD and reproduction traits were generally negligible. In addition, moderate unfavorable (negative) genetic correlations were found between adult CFW and ewe reproduction traits. This study indicates that selecting finer fleeces will yield little to no change in ewe reproduction traits, whereas heavier fleeces are related to reduced ewe reproductive performance. On the other hand, genetically heavier yearling ewes will display greater reproductive performance.