Focal Ischemic Injury to the Early Neonatal Rat Brain Models Cognitive and Motor Deficits with Associated Histopathological Outcomes Relevant to Human Neonatal Brain Injury.

Neonatal arterial ischemic stroke is one of the more severe birth complications. The injury can result in extensive neurological damage and is robustly associated with later diagnoses of cerebral palsy (CP). An important part of efforts to develop new therapies include the on-going refinement and understanding of animal models that capture relevant clinical features of neonatal brain injury leading to CP. The potent vasoconstrictor peptide, Endothelin-1 (ET-1), has previously been utilised in animal models to reduce local blood flow to levels that mimic ischemic stroke. Our previous work in this area has shown that it is an effective and technically simple approach for modelling ischemic injury at very early neonatal ages, resulting in stable deficits in motor function. Here, we aimed to extend this model to also examine the impact on cognitive function. We show that focal delivery of ET-1 to the cortex of Sprague Dawley rats on postnatal day 0 (P0) resulted in impaired learning in a touchscreen-based test of visual discrimination and correlated with important clinical features of CP including damage to large white matter structures.

Human Neural Organoid Microphysiological Systems Show the Building Blocks Necessary for Basic Learning and Memory.

Brain Microphysiological Systems including neural organoids derived from human induced pluripotent stem cells offer a unique lens to study the intricate workings of the human brain. This paper investigates the foundational elements of learning and memory in neural organoids, also known as Organoid Intelligence by quantifying immediate early gene expression, synaptic plasticity, neuronal network dynamics, and criticality to demonstrate the utility of these organoids in basic science research. Neural organoids showed synapse formation, glutamatergic and GABAergic receptor expression, immediate early gene expression basally and evoked, functional connectivity, criticality, and synaptic plasticity in response to theta-burst stimulation. In addition, pharmacological interventions on GABAergic and glutamatergic receptors, and input specific theta-burst stimulation further shed light on the capacity of neural organoids to mirror synaptic modulation and short-term potentiation, demonstrating their potential as tools for studying neurophysiological and neurological processes and informing therapeutic strategies for diseases.

Toward a nomenclature consensus for diverse intelligent systems: Call for collaboration.

Disagreements about language use are common both between and within fields. Where interests require multidisciplinary collaboration or the field of research has the potential to impact society at large, it becomes critical to minimize these disagreements where possible. The development of diverse intelligent systems, regardless of the substrate (e.g., silicon vs. biology), is a case where both conditions are met. Significant advancements have occurred in the development of technology progressing toward these diverse intelligence systems. Whether progress is silicon based, such as the use of large language models, or through synthetic biology methods, such as the development of organoids, a clear need for a community-based approach to seeking consensus on nomenclature is now vital. Here, we welcome collaboration from the wider scientific community, proposing a pathway forward to achieving this intention, highlighting key terms and fields of relevance, and suggesting potential consensus-making methods to be applied.

Critical dynamics arise during structured information presentation within embodied in vitro neuronal networks.

Understanding how brains process information is an incredibly difficult task. Amongst the metrics characterising information processing in the brain, observations of dynamic near-critical states have generated significant interest. However, theoretical and experimental limitations associated with human and animal models have precluded a definite answer about when and why neural criticality arises with links from attention, to cognition, and even to consciousness. To explore this topic, we used an in vitro neural network of cortical neurons that was trained to play a simplified game of 'Pong' to demonstrate Synthetic Biological Intelligence (SBI). We demonstrate that critical dynamics emerge when neural networks receive task-related structured sensory input, reorganizing the system to a near-critical state. Additionally, better task performance correlated with proximity to critical dynamics. However, criticality alone is insufficient for a neuronal network to demonstrate learning in the absence of additional information regarding the consequences of previous actions. These findings offer compelling support that neural criticality arises as a base feature of incoming structured information processing without the need for higher order cognition.

The technology, opportunities, and challenges of Synthetic Biological Intelligence.

Integrating neural cultures developed through synthetic biology methods with digital computing has enabled the early development of Synthetic Biological Intelligence (SBI). Recently, key studies have emphasized the advantages of biological neural systems in some information processing tasks. However, neither the technology behind this early development, nor the potential ethical opportunities or challenges, have been explored in detail yet. Here, we review the key aspects that facilitate the development of SBI and explore potential applications. Considering these foreseeable use cases, various ethical implications are proposed. Ultimately, this work aims to provide a robust framework to structure ethical considerations to ensure that SBI technology can be both researched and applied responsibly.

First Organoid Intelligence (OI) workshop to form an OI community.

The brain is arguably the most powerful computation system known. It is extremely efficient in processing large amounts of information and can discern signals from noise, adapt, and filter faulty information all while running on only 20 watts of power. The human brain's processing efficiency, progressive learning, and plasticity are unmatched by any computer system. Recent advances in stem cell technology have elevated the field of cell culture to higher levels of complexity, such as the development of three-dimensional (3D) brain organoids that recapitulate human brain functionality better than traditional monolayer cell systems. Organoid Intelligence (OI) aims to harness the innate biological capabilities of brain organoids for biocomputing and synthetic intelligence by interfacing them with computer technology. With the latest strides in stem cell technology, bioengineering, and machine learning, we can explore the ability of brain organoids to compute, and store given information (input), execute a task (output), and study how this affects the structural and functional connections in the organoids themselves. Furthermore, understanding how learning generates and changes patterns of connectivity in organoids can shed light on the early stages of cognition in the human brain. Investigating and understanding these concepts is an enormous, multidisciplinary endeavor that necessitates the engagement of both the scientific community and the public. Thus, on Feb 22-24 of 2022, the Johns Hopkins University held the first Organoid Intelligence Workshop to form an OI Community and to lay out the groundwork for the establishment of OI as a new scientific discipline. The potential of OI to revolutionize computing, neurological research, and drug development was discussed, along with a vision and roadmap for its development over the coming decade.

In vitro neurons learn and exhibit sentience when embodied in a simulated game-world.

Integrating neurons into digital systems may enable performance infeasible with silicon alone. Here, we develop DishBrain, a system that harnesses the inherent adaptive computation of neurons in a structured environment. In vitro neural networks from human or rodent origins are integrated with in silico computing via a high-density multielectrode array. Through electrophysiological stimulation and recording, cultures are embedded in a simulated game-world, mimicking the arcade game "Pong." Applying implications from the theory of active inference via the free energy principle, we find apparent learning within five minutes of real-time gameplay not observed in control conditions. Further experiments demonstrate the importance of closed-loop structured feedback in eliciting learning over time. Cultures display the ability to self-organize activity in a goal-directed manner in response to sparse sensory information about the consequences of their actions, which we term synthetic biological intelligence. Future applications may provide further insights into the cellular correlates of intelligence.

Integrating levels of bone growth control: From stem cells to body proportions.

The study of the mechanisms controlling organ size during development and regeneration is critical to understanding how complex life arises from cooperating single cells. Long bones are powerful models in this regard, as their size depends on a scaffold made from another tissue (cartilage, composed of chondrocytes), and both tissues interact during the growth period. Investigating long bone growth offers a valuable window into the processes that integrate internal and external cues to yield finely controlled size of organs. Within the cellular and molecular pathways that control bone growth, the regulation of stem-cell renewal, along with amplification and differentiation of their progeny, are key to understanding normal and perturbed long-bone development. The phenomenon of "catch-up" growth-where cellular hyperproliferation occurs following injury to restore a normal growth trajectory-reveals key aspects of this regulation, such as the fact that bone growth is target-seeking. The control mechanisms that lead to this behavior are either bottom-up or top-down, and the interaction between these modes is likely critical to achieve a highly nuanced, yet flexible, degree of control. The role of cartilage-intrinsic mechanisms has been well studied, establishing a very solid groundwork for this field. However, addressing the unanswered questions of bone growth arguably requires new hypotheses and approaches. Future research could for example address to what extent extrinsic signals and cells, as well as communication with other tissues, modulate intra-limb and inter-organ growth coordination. This article is categorized under: Adult Stem Cells, Tissue Renewal, and Regeneration > Tissue Stem Cells and Niches Establishment of Spatial and Temporal Patterns > Regulation of Size, Proportion, and Timing Vertebrate Organogenesis > Musculoskeletal and Vascular.

Long-Term Motor Deficit and Diffuse Cortical Atrophy Following Focal Cortical Ischemia in Athymic Rats.

Development of new stroke therapies requires animal models that recapitulate the pathophysiological and functional consequences of ischemic brain damage over time-frames relevant to the therapeutic intervention. This is particularly relevant for the rapidly developing area of stem cell therapies, where functional replacement of circuitry will require maturation of transplanted human cells over months. An additional challenge is the establishment of models of ischemia with stable behavioral phenotypes in chronically immune-suppressed animals to allow for long-term survival of human cell grafts. Here we report that microinjection of endothelin-1 into the sensorimotor cortex of athymic rats results in ischemic damage with a sustained deficit in function of the contralateral forepaw that persists for up to 9 months. The histological post-mortem analysis revealed chronic and diffuse atrophy of the ischemic cortical hemisphere that continued to progress over 9 months. Secondary atrophy remote to the primary site of injury and its relationship with long-term cognitive and functional decline is now recognized in human populations. Thus, focal cortical infarction in athymic rats mirrors important pathophysiological and functional features relevant to human stroke, and will be valuable for assessing efficacy of stem cell based therapies.

Local Injection of Endothelin-1 in the Early Neonatal Rat Brain Models Ischemic Damage Associated with Motor Impairment and Diffuse Loss in Brain Volume.

Cerebral palsy is an irreversible movement disorder resulting from cerebral damage sustained during prenatal or neonatal brain development. As survival outcomes for preterm injury improve, there is increasing need to model ischemic injury at earlier neonatal time-points to better understand the subsequent pathological consequences. Here we demonstrate a novel neonatal ischemic model using focal administration of the potent vasoconstrictor peptide, endothelin-1 (ET-1), in newborn rats. The functional and histopathological outcomes compare favourably to those reported following the widely used hypoxic ischemia (HI) model. These include a robust motor deficit sustained into adulthood and recapitulation of hallmark features of preterm human brain injury, including atrophy of subcortical white matter and periventricular fiber bundles. Compared to procedures involving carotid artery manipulation and periods of hypoxia, the ET-1 ischemia model represents a rapid and technically simplified model more amenable to larger cohorts and with the potential to direct the locus of ischemic damage to specific brain areas.