Neuroplasticity: Can the Brain Rewire Itself?

Identifying and investigating emergent behaviour in neural systems

This manuscript distil theoretical approaches to emergence into a practical framework for assessing system behaviour focussed on “novelty” as a necessary condition for emergence and identifies a range of ways in which novelty can arise.

NEUROPLASTICITY ACROSS THE LIFESPAN: MECHANISMS, MODULATORS, MALADAPTATION AND TRANSLATIONAL FRONTIERS

Neuroplasticity, the capacity of the nervous system to alter its structure, function and connectivity in response to intrinsic and extrinsic stimuli, has moved from a developmental curiosity to a central organising principle of contemporary neuroscience and a plausible therapeutic target across neurology, psychiatry, pharmacology and rehabilitation medicine. This condensed review synthesises current mechanistic and translational evidence within a single integrated framework. Four interdependent pillars of plasticity are delineated: synaptic modification, comprising long-term potentiation, long term depression, spike-timing dependence, metaplasticity and homeostatic scaling; structural remodelling, comprising spine turnover, dendritic and axonal growth, pruning and activity-dependent myelination; neurogenesis; and system-level functional reorganisation, comprising map plasticity, vicariation and diaschisis. These neuron-centred processes are permitted or constrained by a supporting tissue environment of astrocytes, microglia, oligodendrocytes, extracellular matrix and the neurovascular unit, and converge on a common molecular substrate dominated by calcium-dependent glutamatergic signalling, brain-derived neurotrophic factor-TrkB transduction, transcriptional and epigenetic control, and neurosteroid modulation. Plastic capacity follows a non-monotonic lifespan trajectory, being high and experience expectant during critical periods, progressively gated in adulthood, and attenuated but not abolished in senescence. Critically, plasticity is directionally neutral: identical mechanisms underwrite skill acquisition and recovery on the one hand, and central sensitisation, addiction, dystonia and epileptogenesis on the other. The current interventional armamentarium is appraised, spanning task-specific rehabilitation, aerobic exercise, cognitive and social enrichment, structured psychological techniques including clinical hypnosis, sleep and dietary optimisation, non-invasive and paired neuromodulation, plasticity-promoting pharmacology, brain-computer interfaces and artificial-intelligence-guided personalisation, with the maturity of supporting evidence graded for each. Persistent obstacles include biomarker non equivalence, heterogeneity of dose and timing, short follow-up, and unresolved ethical questions concerning equitable access, neural data privacy and the therapy-enhancement boundary. The decisive translational challenge is no longer whether plasticity can be induced, but whether it can be reliably steered.

The mPFC-reuniens-hippocampus pathway links brain circuitry and neural plasticity in antidepressant response

The pathophysiology of depression involves multiple biological processes, including circuit dysfunction and impaired neuroplasticity, yet an integrative view linking these processes remains elusive. Here, we identify a convergent circuit for antidepressant response and plasticity modulation. We demonstrate that chemogenetic activation of the infralimbic cortex (IL) exerts rapid antidepressant-like effects across multiple behavioral domains in a mouse model of stress-induced depression. IL stimulation exerts top-down control over the hippocampus, enhancing structural plasticity, restoring long-term potentiation deficits and improving state-dependent network dynamics in the ventral hippocampus (vHIPP). We identify the thalamic nucleus reuniens (RE) as a necessary mediator of these effects. Notably, direct inhibition of RE, its inputs from IL or projections to vHIPP, blocks both IL stimulation-induced antidepressant response and the therapeutic and neuroplastic effects of ketamine. Our findings demonstrate that the functional IL → RE→vHIPP circuit plays a central role in the antidepressant response, linking circuit activity, hippocampal plasticity, and depressive-like behaviors. Neural mechanisms underlying depression are not fully understood. This study identifies a prefrontal–thalamic–hippocampal circuit that links antidepressant-like behavior with restored neural plasticity and is required for ketamine’s behavioral and neuroplastic effects in mice.

Neuromodulation for restoring and amplifying brain function.

Neuromodulators of orbitofrontal cortex function: A review of endocannabinoid, neurotrophin, and cell adhesion systems

The ability to incorporate changing information from the environment into our actions is essential for flexible behavior. The orbitofrontal cortex (OFC) is involved in integrating new information into on-going and future actions. As elsewhere in the brain, neuronal activity in the OFC is subject to fine-tuning by neurotransmitters like serotonin, dopamine, and norepinephrine. The purpose of this review is to highlight other neuromodulatory factors that have received less attention but are also potent regulators of OFC-dependent decision making. Specifically, we summarize the impacts of endocannabinoids, the neurotrophin Brain-derived Neurotrophic Factor, and cell adhesion systems in both medial and lateral compartments of the OFC. Generally speaking, perturbations to these systems disrupt flexible decision making, resulting in behaviors resembling poor learning, perseveration, and deferral to habitual actions. Understanding the molecular mechanisms supporting OFC function may drive the discovery of novel therapeutic approaches to alleviating these symptoms in various neuropsychiatric disorders.

On the meaning of “plasticity” in neuroscience and mental health research and its relation to the action of psychedelic therapy

First-line dictionary definitions of “plasticity” describe it as the ability (of a thing) to be shaped or molded; we call this “plasticity proper” (PP). In neuroscience, however, “neural plasticity” or “neuroplasticity” is defined as an induced change in brain function or structure. These two plasticities are not the same. Several popular biomarkers of neuroplasticity index part of an evoked process, often linked to learning. Paradoxically, these processes often bias phenotypic canalization, the opposite of phenotypic plasticity. Recognizing this paradox puts into question the custom of using “plasticity” as a shorthand for all neuroplastic phenomena. This custom risks an overgeneralization fallacy and the conflation of assays of evoked brain changes with plasticity proper. We also question extrapolating from any biomarker of neuroplasticity to improved mental health, whether it be aligned with plasticity proper or not. The relationship between the two is, logically, context dependent . As a resolution, we propose a new construct, “mediational and recalibrative plasticity” (MR-P) and show how markers of it can describe and predict examples of phenotypic plasticity, where those phenotypes are states and traits relevant to mental health. In contrast to many markers of neuroplasticity, MR-P is aligned with plasticity proper.