Lasting dynamic effects of the psychedelic 2,5-dimethoxy-4-iodoamphetamine ((±)-DOI) on cognitive flexibility.

Psychedelic drugs can aid fast and lasting remission from various neuropsychiatric disorders, though the underlying mechanisms remain unclear. Preclinical studies suggest serotonergic psychedelics enhance neuronal plasticity, but whether neuroplastic changes can also be seen at cognitive and behavioural levels is unexplored. Here we show that a single dose of the psychedelic 2,5-dimethoxy-4-iodoamphetamine ((±)-DOI) affects structural brain plasticity and cognitive flexibility in young adult mice beyond the acute drug experience. Using ex vivo magnetic resonance imaging, we show increased volumes of several sensory and association areas one day after systemic administration of 2 mgkg-1 (±)-DOI. We then demonstrate lasting effects of (±)-DOI on cognitive flexibility in a two-step probabilistic reversal learning task where 2 mgkg-1 (±)-DOI improved the rate of adaptation to a novel reversal in task structure occurring one-week post-treatment. Strikingly, (±)-DOI-treated mice started learning from reward omissions, a unique strategy not typically seen in mice in this task, suggesting heightened sensitivity to previously overlooked cues. Crucially, further experiments revealed that (±)-DOI's effects on cognitive flexibility were contingent on the timing between drug treatment and the novel reversal, as well as on the nature of the intervening experience. (±)-DOI's facilitation of both cognitive adaptation and novel thinking strategies may contribute to the clinical benefits of psychedelic-assisted therapy, particularly in cases of perseverative behaviours and a resistance to change seen in depression, anxiety, or addiction. Furthermore, our findings highlight the crucial role of time-dependent neuroplasticity and the influence of experiential factors in shaping the therapeutic potential of psychedelic interventions for impaired cognitive flexibility.

Dopamine-independent effect of rewards on choices through hidden-state inference.

Dopamine is implicated in adaptive behavior through reward prediction error (RPE) signals that update value estimates. There is also accumulating evidence that animals in structured environments can use inference processes to facilitate behavioral flexibility. However, it is unclear how these two accounts of reward-guided decision-making should be integrated. Using a two-step task for mice, we show that dopamine reports RPEs using value information inferred from task structure knowledge, alongside information about reward rate and movement. Nonetheless, although rewards strongly influenced choices and dopamine activity, neither activating nor inhibiting dopamine neurons at trial outcome affected future choice. These data were recapitulated by a neural network model where cortex learned to track hidden task states by predicting observations, while basal ganglia learned values and actions via RPEs. This shows that the influence of rewards on choices can stem from dopamine-independent information they convey about the world's state, not the dopaminergic RPEs they produce.

Lights, fiber, action! A primer on in vivo fiber photometry.

Fiber photometry is a key technique for characterizing brain-behavior relationships in vivo. Initially, it was primarily used to report calcium dynamics as a proxy for neural activity via genetically encoded indicators. This generated new insights into brain functions including movement, memory, and motivation at the level of defined circuits and cell types. Recently, the opportunity for discovery with fiber photometry has exploded with the development of an extensive range of fluorescent sensors for biomolecules including neuromodulators and peptides that were previously inaccessible in vivo. This critical advance, combined with the new availability of affordable "plug-and-play" recording systems, has made monitoring molecules with high spatiotemporal precision during behavior highly accessible. However, while opening exciting new avenues for research, the rapid expansion in fiber photometry applications has occurred without coordination or consensus on best practices. Here, we provide a comprehensive guide to help end-users execute, analyze, and suitably interpret fiber photometry studies.

Impact of mangrove forest structure and landscape on macroplastics capture.

Complex networks of above-ground roots and trunks make mangrove forests trap plastic litter. We tested how macroplastics relate to tree biomass, root abundance, mangrove geomorphology and river mouth proximity, surveying landward and seaward margins of seven forests in the Philippines, a global hotspot for marine plastic pollution. Macroplastics were abundant (mean ± s.e.: 1.1 ± 0.22 items m-2; range: 0.05 ± 0.05 to 3.79 ± 1.91), greatest at the landward zone (mean ± s.e.: 1.60 ± 0.41 m-2) and dominated by land-derived items (sachets, bags). Plastic abundance and weight increased with proximity to river mouths, with root abundance predicting plastic litter surface area (i.e., the cumulative sum of all the surface areas of each plastic element per plot). The study confirms rivers are a major pathway for marine plastic pollution, with mangrove roots are the biological attribute that regulate litter retention. The results suggest land-based waste management that prevent plastics entering rivers will reduce marine plastic pollution in Southeast Asia.

Neural responses in macaque prefrontal cortex are linked to strategic exploration.

Humans have been shown to strategically explore. They can identify situations in which gathering information about distant and uncertain options is beneficial for the future. Because primates rely on scarce resources when they forage, they are also thought to strategically explore, but whether they use the same strategies as humans and the neural bases of strategic exploration in monkeys are largely unknown. We designed a sequential choice task to investigate whether monkeys mobilize strategic exploration based on whether information can improve subsequent choice, but also to ask the novel question about whether monkeys adjust their exploratory choices based on the contingency between choice and information, by sometimes providing the counterfactual feedback about the unchosen option. We show that monkeys decreased their reliance on expected value when exploration could be beneficial, but this was not mediated by changes in the effect of uncertainty on choices. We found strategic exploratory signals in anterior and mid-cingulate cortex (ACC/MCC) and dorsolateral prefrontal cortex (dlPFC). This network was most active when a low value option was chosen, which suggests a role in counteracting expected value signals, when exploration away from value should to be considered. Such strategic exploration was abolished when the counterfactual feedback was available. Learning from counterfactual outcome was associated with the recruitment of a different circuit centered on the medial orbitofrontal cortex (OFC), where we showed that monkeys represent chosen and unchosen reward prediction errors. Overall, our study shows how ACC/MCC-dlPFC and OFC circuits together could support exploitation of available information to the fullest and drive behavior towards finding more information through exploration when it is beneficial.

Glutamatergic dysfunction leads to a hyper-dopaminergic phenotype through deficits in short-term habituation: a mechanism for aberrant salience.

Psychosis in disorders like schizophrenia is commonly associated with aberrant salience and elevated striatal dopamine. However, the underlying cause(s) of this hyper-dopaminergic state remain elusive. Various lines of evidence point to glutamatergic dysfunction and impairments in synaptic plasticity in the etiology of schizophrenia, including deficits associated with the GluA1 AMPAR subunit. GluA1 knockout (Gria1-/-) mice provide a model of impaired synaptic plasticity in schizophrenia and exhibit a selective deficit in a form of short-term memory which underlies short-term habituation. As such, these mice are unable to reduce attention to recently presented stimuli. In this study we used fast-scan cyclic voltammetry to measure phasic dopamine responses in the nucleus accumbens of Gria1-/- mice to determine whether this behavioral phenotype might be a key driver of a hyper-dopaminergic state. There was no effect of GluA1 deletion on electrically-evoked dopamine responses in anaesthetized mice, demonstrating normal endogenous release properties of dopamine neurons in Gria1-/- mice. Furthermore, dopamine signals were initially similar in Gria1-/- mice compared to controls in response to both sucrose rewards and neutral light stimuli. They were also equally sensitive to changes in the magnitude of delivered rewards. In contrast, however, these stimulus-evoked dopamine signals failed to habituate with repeated presentations in Gria1-/- mice, resulting in a task-relevant, hyper-dopaminergic phenotype. Thus, here we show that GluA1 dysfunction, resulting in impaired short-term habituation, is a key driver of enhanced striatal dopamine responses, which may be an important contributor to aberrant salience and psychosis in psychiatric disorders like schizophrenia.

Microstimulation of Interstitial Nucleus of Cajal Evokes Directionally Disconjugate Eye Movements in Monkeys With Pattern Strabismus.

Purpose: Pattern strabismus is characterized by a horizontal misalignment of the eyes that varies with vertical eye position. This disorder has traditionally been described, and treated, as overaction or underaction of the oblique muscles. In recent years, evidence has accumulated that indicate that the disorder is associated with abnormal cross-talk between brainstem pathways that contribute to the horizontal and vertical components of eye movements. The present study was designed to investigate the hypothesis that the key abnormalities are at the level of, or downstream from, the interstitial nucleus of Cajal (INC). Methods: Microstimulation was applied to the INC in two mature rhesus monkeys with "A" pattern strabismus that was experimentally induced in infancy. We asked whether the evoked movements would be vertical and conjugate, as has been previously reported in normal monkeys, or would be directionally disconjugate (i.e. with oblique or horizontal movement observed for at least one eye). Results: Evoked movements were conjugate and vertical for a minority of sites but, for most sites, the evoked movements were directionally disconjugate. Moreover, there was typically a convergent change in horizontal strabismus when the evoked movements were upward and a divergent change when the evoked movements were downward. Conclusions: Microstimulation of INC in monkeys with A-pattern strabismus evokes movements with the expected directional disconjugacies, implying that the key neural abnormalities are within, or downstream from, this structure. High site-to-site variability in the conjugacy/disconjugacy of evoked movements rules out the hypothesis that the abnormalities are solely peripheral.

Complementary task representations in hippocampus and prefrontal cortex for generalizing the structure of problems.

Humans and other animals effortlessly generalize prior knowledge to solve novel problems, by abstracting common structure and mapping it onto new sensorimotor specifics. To investigate how the brain achieves this, in this study, we trained mice on a series of reversal learning problems that shared the same structure but had different physical implementations. Performance improved across problems, indicating transfer of knowledge. Neurons in medial prefrontal cortex (mPFC) maintained similar representations across problems despite their different sensorimotor correlates, whereas hippocampal (dCA1) representations were more strongly influenced by the specifics of each problem. This was true for both representations of the events that comprised each trial and those that integrated choices and outcomes over multiple trials to guide an animal's decisions. These data suggest that prefrontal cortex and hippocampus play complementary roles in generalization of knowledge: PFC abstracts the common structure among related problems, and hippocampus maps this structure onto the specifics of the current situation.

Reduced activity of vertically acting motoneurons during convergence.

Previous studies have revealed unexpected relationships between the firing rates of horizontally acting motoneurons and vergence. During a vergence task, for example, antidromically identified abducens internuclear neurons show a negative correlation between vergence angle and firing rate, which is the opposite of the modulation displayed by the medial rectus motoneurons to which they project. For a given horizontal eye position, medial rectus motoneurons discharge at a higher rate if the eyes are converged than if the same eye position is reached during a task that requires version; paradoxically, however, the horizontal rectus eye muscles show corelaxation during vergence. These complex and unexpected relationships inspired the present author to investigate whether the tonic firing rates of vertically acting motoneurons in oculomotor nucleus are correlated with vergence angle. Monkeys were trained to fixate a single, randomly selected, visual target among an array of 60 red plus-shaped LEDs, arranged at 12 different distances in three-dimensional space. The targets were arranged to permit dissociation of vertical eye position and vergence angle. Here I report, for the first time, that most vertically acting motoneurons in oculomotor nucleus show a significant negative correlation between tonic firing rate and vergence angle. This suggests the possibility that there may be a general corelaxation of extraocular muscles during vergence.NEW & NOTEWORTHY An array of 60 plus-shaped LEDs, positioned at various locations in three-dimensional space, was used to elicit conjugate and disjunctive saccades while single neurons in oculomotor nucleus were recorded from rhesus monkeys. This study demonstrates that most vertically acting motoneurons in oculomotor nucleus discharge at a lower rate when the eyes are converged.

Microplastics alter multiple biological processes of marine benthic fauna.

Marine sediments are a sink for microplastics, making seabed organisms particularly exposed. We used meta-analysis to reveal general patterns in a surge in experimental studies and to test for microplastic impact on biological processes including invertebrate feeding, survival and energetics. Using Hedge's effect size (g), which assesses the mean response of organisms exposed to microplastics compared to control groups, we found negative impacts (significant negative g values) across all life stages (overall effect size (g) = -0.57 95 % CI [-0.76, -0.38]), with embryos most strongly affected (g = -1.47 [-2.21, -0.74]). Six of seven biological process rates were negatively impacted by microplastic exposure, including development, reproduction, growth and feeding. Survival strongly decreased (g = -0.69 [-1.21, -0.17]), likely due to cumulative effects on other processes such as feeding and growth. Among feeding habits, omnivores and deposit feeders were most negatively impacted (g = -0.93 [-1.69, -0.16] and -0.92 [-1.53, -0.31], respectively). The study incorporated the first meta-analysis to contrast the effects of leachates, virgin, aged and contaminated particles. Exposure to leachates had by far the strongest negative effects (g = -0.93 [-1.35, -0.51]), showing studies of contaminants and leachates are critical to future research. Overall, our meta-analysis reveals stronger and more consistent negative impacts of microplastics on seabed invertebrates than recorded for other marine biota. Seabed invertebrates are numerous and diverse, and crucial to bottom-up processes, including nutrient remineralisation, bentho-pelagic coupling and energy transfer through the ocean food web. Marine sediments will store microplastics over long timescales. The reveal that microplastics impinge on multiple fundamental biological processes of seabed fauna implies plastic pollution could have significant and enduring effects on the functioning of the ocean.

Elucidating the surface macroplastic load, types and distribution in mangrove areas around Cebu Island, Philippines and its policy implications.

The Philippines is identified as one of the major marine plastic litter polluters in the world with a discharge of approximately 0.75 million tons of marine plastic debris per year. However, the extent of the plastic problem is yet to be defined systematically because of limited research. Thus, this study aims to quantify plastic litter occurrence in mangrove areas as they function as sinks for plastic litter due to their inherent nature of trapping plastics. To define the extent of marine plastic pollution on an island scale, mangrove areas in 14 municipalities around Cebu Island were sampled, with 3 to 9 transects in each site depending on the length of coastline covered by mangroves. Sampling and characterization of both plastics and the mangrove ecosystem was performed in three locations along the transect - landward, middle, and seaward. A total of 4501 plastic items were sampled throughout the study sites with an average of 1.29 ± 0.67 items/m2 (18.07 ± 8.79 g/m2). The average distribution of plastic loads were 2.68 ± 1.9 items/m2 (38.52 ± 25.35 g/m2), 0.27 ± 0.10 items/m2 (6.65 ± 4.67 g/m2), and 0.94 ± 0.61 items/m2 (9.04 ± 4.28 g/m2) for the landward, middle, and seaward locations, respectively. The most frequent plastic types found were i) packaging, ii) plastic bags and iii) plastic fragments. The plastic loads and types suggest that most plastic wastes trapped in mangroves come from the nearby communities. Fishing-related plastics originated from the sea and were transported across the mangrove breadth. The findings confirm that mangroves are major traps of plastic litter that might adversely affect the marine ecosystem. The study underscores the urgent need for waste mitigation measures, including education, community engagement, infrastructure, technological solutions and supporting policies.

Nucleus accumbens D1-receptors regulate and focus transitions to reward-seeking action.

It is well established that dopamine transmission is integral in mediating the influence of reward expectations on reward-seeking actions. However, the precise causal role of dopamine transmission in moment-to-moment reward-motivated behavioral control remains contentious, particularly in contexts where it is necessary to refrain from responding to achieve a beneficial outcome. To examine this, we manipulated dopamine transmission pharmacologically as rats performed a Go/No-Go task that required them to either make or withhold action to gain either a small or large reward. D1R Stimulation potentiated cue-driven action initiation, including fast impulsive actions on No-Go trials. By contrast, D1R blockade primarily disrupted the successful completion of Go trial sequences. Surprisingly, while after global D1R blockade this was characterized by a general retardation of reward-seeking actions, nucleus accumbens core (NAcC) D1R blockade had no effect on the speed of action initiation or impulsive actions. Instead, fine-grained analyses showed that this manipulation decreased the precision of animals' goal-directed actions, even though they usually still followed the appropriate response sequence. Strikingly, such "unfocused" responding could also be observed off-drug, particularly when only a small reward was on offer. These findings suggest that the balance of activity at NAcC D1Rs plays a key role in enabling the rapid activation of a focused, reward-seeking state to enable animals to efficiently and accurately achieve their goal.

Remote ischemic conditioning in necrotizing enterocolitis: study protocol of a multi-center phase II feasibility randomized controlled trial.

PURPOSE: Remote ischemic conditioning (RIC) is a maneuver involving brief cycles of ischemia reperfusion in an individual's limb. In the early stage of experimental NEC, RIC decreased intestinal injury and prolonged survival by counteracting the derangements in intestinal microcirculation. A single-center phase I study demonstrated that the performance of RIC was safe in neonates with NEC. The aim of this phase II RCT was to evaluate the safety and feasibility of RIC, to identify challenges in recruitment, retainment, and to inform a phase III RCT to evaluate efficacy. METHODS: RIC will be performed by trained research personnel and will consist of four cycles of limb ischemia (4-min via cuff inflation) followed by reperfusion (4-min via cuff deflation), repeated on two consecutive days post randomization. The primary endpoint of this RCT is feasibility and acceptability of recruiting and randomizing neonates within 24 h from NEC diagnosis as well as masking and completing the RIC intervention. RESULTS: We created a novel international consortium for this trial and created a consensus on the diagnostic criteria for NEC and protocol for the trial. The phase II multicenter-masked feasibility RCT will be conducted at 12 centers in Canada, USA, Sweden, The Netherlands, UK, and Spain. The inclusion criteria are: gestational age < 33 weeks, weight ≥ 750 g, NEC receiving medical treatment, and diagnosis established within previous 24 h. Neonates will be randomized to RIC (intervention) or no-RIC (control) and will continue to receive standard management of NEC. We expect to recruit and randomize 40% of eligible patients in the collaborating centers (78 patients; 39/arm) in 30 months. Bayesian methods will be used to combine uninformative prior distributions with the corresponding observed proportions from this trial to determine posterior distributions for parameters of feasibility. CONCLUSIONS: The newly established NEC consortium has generated novel data on NEC diagnosis and defined the feasibility parameters for the introduction of a novel treatment in NEC. This phase II RCT will inform a future phase III RCT to evaluate the efficacy and safety of RIC in early-stage NEC.

Open-source, Python-based, hardware and software for controlling behavioural neuroscience experiments.

Laboratory behavioural tasks are an essential research tool. As questions asked of behaviour and brain activity become more sophisticated, the ability to specify and run richly structured tasks becomes more important. An increasing focus on reproducibility also necessitates accurate communication of task logic to other researchers. To these ends, we developed pyControl, a system of open-source hardware and software for controlling behavioural experiments comprising a simple yet flexible Python-based syntax for specifying tasks as extended state machines, hardware modules for building behavioural setups, and a graphical user interface designed for efficiently running high-throughput experiments on many setups in parallel, all with extensive online documentation. These tools make it quicker, easier, and cheaper to implement rich behavioural tasks at scale. As important, pyControl facilitates communication and reproducibility of behavioural experiments through a highly readable task definition syntax and self-documenting features. Here, we outline the system's design and rationale, present validation experiments characterising system performance, and demonstrate example applications in freely moving and head-fixed mouse behaviour.

Towards progressive regulatory approaches for agricultural applications of animal biotechnology.

Traditional breeding techniques, applied incrementally over thousands of years, have yielded huge benefits in the characteristics of agricultural animals. This is a result of significant, measurable changes to the genomes of those animal species and breeds. Genome editing techniques may now be applied to achieve targeted DNA sequence alterations, with the potential to affect traits of interest to production of agricultural animals in just one generation. New opportunities arise to improve characteristics difficult to achieve or not amenable to traditional breeding, including disease resistance, and traits that can improve animal welfare, reduce environmental impact, or mitigate impacts of climate change. Countries and supranational institutions are in the process of defining regulatory approaches for genome edited animals and can benefit from sharing approaches and experiences to institute progressive policies in which regulatory oversight is scaled to the particular level of risk involved. To facilitate information sharing and discussion on animal biotechnology, an international community of researchers, developers, breeders, regulators, and communicators recently held a series of seven virtual workshop sessions on applications of biotechnology for animal agriculture, food and environmental safety assessment, regulatory approaches, and market and consumer acceptance. In this report, we summarize the topics presented in the workshop sessions, as well as discussions coming out of the breakout sessions. This is framed within the context of past and recent scientific and regulatory developments. This is a pivotal moment for determination of regulatory approaches and establishment of trust across the innovation through-chain, from researchers, developers, regulators, breeders, farmers through to consumers.

5-HT2C receptor perturbation has bidirectional influence over instrumental vigour and restraint.

The serotonin (5-HT) system, particularly the 5-HT2C receptor, has consistently been implicated in behavioural control. However, while some studies have focused on the role 5-HT2C receptors play in regulating motivation to work for reward, others have highlighted its importance in response restraint. To date, it is unclear how 5-HT transmission at this receptor regulates the balance of response invigoration and restraint in anticipation of future reward. In addition, it remains to be established how 5-HT2C receptors gate the influence of internal versus cue-driven processes over reward-guided actions. To elucidate these issues, we investigated the effects of administering the 5-HT2C receptor antagonist SB242084, both systemically and directly into the nucleus accumbens core (NAcC), in rats performing a Go/No-Go task for small or large rewards. The results were compared to the administration of d-amphetamine into the NAcC, which has previously been shown to promote behavioural activation. Systemic perturbation of 5-HT2C receptors-but crucially not intra-NAcC infusions-consistently boosted rats' performance and instrumental vigour on Go trials when they were required to act. Concomitantly, systemic administration also reduced their ability to withhold responding for rewards on No-Go trials, particularly late in the holding period. Notably, these effects were often apparent only when the reward on offer was small. By contrast, inducing a hyperdopaminergic state in the NAcC with d-amphetamine strongly impaired response restraint on No-Go trials both early and late in the holding period, as well as speeding action initiation. Together, these findings suggest that 5-HT2C receptor transmission, outside the NAcC, shapes the vigour of ongoing goal-directed action as well as the likelihood of responding as a function of expected reward.

Distinct roles for dopamine clearance mechanisms in regulating behavioral flexibility.

Dopamine plays a crucial role in adaptive behavior, and dysfunctional dopamine is implicated in multiple psychiatric conditions characterized by inflexible or inconsistent choices. However, the precise relationship between dopamine and flexible decision making remains unclear. One reason is that, while many studies have focused on the activity of dopamine neurons, efficient dopamine signaling also relies on clearance mechanisms, notably the dopamine transporter (DAT), which predominates in striatum, and catechol-O-methyltransferase (COMT), which predominates in cortex. The exact locus, extent, and timescale of the effects of DAT and COMT are uncertain. Moreover, there is limited data on how acute disruption of either mechanism affects flexible decision making strategies mediated by cortico-striatal networks. To address these issues, we combined pharmacological modulation of DAT and COMT with electrochemistry and behavior in mice. DAT blockade, but not COMT inhibition, regulated sub-second dopamine release in the nucleus accumbens core, but surprisingly neither clearance mechanism affected evoked release in prelimbic cortex. This was not due to a lack of sensitivity, as both amphetamine and atomoxetine changed the kinetics of sub-second release. In a multi-step decision making task where mice had to respond to reversals in either reward probabilities or the choice sequence to reach the goal, DAT blockade selectively impaired, and COMT inhibition improved, performance after reward reversals, but neither manipulation affected the adaptation of choices after action-state transition reversals. Together, our data suggest that DAT and COMT shape specific aspects of behavioral flexibility by regulating different aspects of the kinetics of striatal and cortical dopamine, respectively.

Defining an orbitofrontal compass: Functional and anatomical heterogeneity across anterior-posterior and medial-lateral axes.

The orbitofrontal cortex (OFC) plays a critical role in the flexible control of behaviors and has been the focus of increasing research interest. However, there have been a number of controversies around the exact theoretical role of the OFC. One potential source of these issues is the comparison of evidence from different studies, particularly across species, which focus on different specific sub-regions within the OFC. Furthermore, there is emerging evidence that there may be functional diversity across the OFC which may account for these theoretical differences. Therefore, in this review we consider evidence supporting functional heterogeneity within the OFC and how it relates to underlying anatomical heterogeneity. We highlight the importance of anatomical and functional distinctions within the traditionally defined OFC subregions across the medial-lateral axis, which are often not differentiated for practical and historical reasons. We then consider emerging evidence of even finer-grained distinctions within these defined subregions along the anterior-posterior axis. These fine-grained anatomical considerations reveal a pattern of dissociable, but often complementary functions within the OFC. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Organization of Afferents along the Anterior-posterior and Medial-lateral Axes of the Rat Orbitofrontal Cortex.

The orbitofrontal cortex (OFC) has been anatomically divided into a number of subregions along its medial-lateral axis, which behavioral research suggests have distinct functions. Recently, evidence has emerged suggesting functional diversity is also present along the anterior-posterior axis of the rodent OFC. However, the patterns of anatomical connections that underlie these differences have not been well characterized. Here, we use the retrograde tracer cholera toxin subunit B (CTB) to simultaneously label the projections into the anterior lateral (ALO), posterior lateral (PLO), and posterior ventral (PVO) portions of the rat OFC. Our methodological approach allowed us to simultaneously compare the density and input patterns into these OFC subdivisions. We observed distinct and topographically organized projection patterns into ALO, PLO, and PVO from the mediodorsal and the submedius nuclei of the thalamus. We also observed different levels of connectivity strength into these OFC subdivisions from the amygdala, motor cortex, sensory cortices and medial prefrontal cortical structures, including medial OFC, infralimbic and prelimbic cortices. Interestingly, while labelling in some of these input regions revealed only a gradient in connectivity strength, other regions seem to project almost exclusively to specific OFC subdivisions. Moreover, differences in input patterns between ALO and PLO were as pronounced as those between PLO and PVO. Together, our results support the existence of distinct anatomical circuits within lateral OFC along its anterior-posterior axis.