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The search for memory is one of the oldest quests in written human history. For at least two millennia, we have tried to understand how we learn and remember. We have gradually converged on the brain and looked inside it to find the basis of knowledge, the trace of memory. The search for memory has been conducted on multiple levels, from the organ to the cell to the synapse, and has been distributed across disciplines with less chronological or intellectual overlap than one might hope. Frequently, the study of the mind and its memories has been severely restricted by technological or philosophical limitations. However, in the last few years, certain technologies have emerged, offering new routes of inquiry into the basis of memory. The 2016 Kavli Futures Symposium was devoted to the past and future of memory studies. At the workshop, participants evaluated the logic and data underlying the existing and emerging theories of memory. In this paper, written in the spirit of the workshop, we briefly review the history of the hunt for memory, summarizing some of the key debates at each level of spatial resolution. We then discuss the exciting new opportunities to unravel the mystery of memory. [ABSTRACT FROM AUTHOR]

The development of new antidepressants has had mixed results over the past decade, with several notable failures. This paper reviews a number of major initiatives in the development of new antidepressant agents. Traditional strategies to build on agents that have monoaminergic effects at the synapse (e.g., vilazodone and ketamine) have been complemented with efforts that have emphasized devices and brain circuits (e.g., deep brain stimulation and transcranial magnetic stimulation) or chemical agents that modulate neuroendocrine systems (e.g., glucocorticoid antagonists, mixed melatonin agonists/serotonin type-2 receptor antagonists). Interestingly, chemical agents, such as onabotulinumtoxin A, may affect brain circuits as well. We present data from recent studies in drug and device development--reviewing progress made, stumbling blocks encountered, and issues that need to be addressed in future studies. [ABSTRACT FROM AUTHOR]

Primary afferent neurotransmission is the fundamental first step in the central processing of sensory stimuli and is controlled by pre- and postsynaptic inhibitory mechanisms. Presynaptic inhibition (PSI) is probably the more powerful form of inhibitory control in all primary afferent fibers. A major mechanism producing afferent PSI is via a channel-mediated depolarization of their intraspinal terminals, which can be recorded extracellularly as a dorsal root potential (DRP). Based on measures of DRP latency it has been inferred that this primary afferent depolarization (PAD) of low-threshold afferents is mediated by minimally trisynaptic pathways with pharmacologically identified GABAergic interneurons forming last-order axo-axonic synapses onto afferent terminals. There is still no “squeaky clean” evidence of this organization. This paper describes recent and historical work that supports the existence of PAD occurring by more direct pathways and with a complex pharmacology that questions the proprietary role of GABA and GABAA receptors in this process. Cholinergic transmission in particular may contribute significantly to PAD, including via direct release from primary afferents. [ABSTRACT FROM AUTHOR]

The evolution of the nervous system progressed through cellular diversification and specialization of functions. Conceptually, the nervous system is composed of electrically excitable neuronal networks connected by chemical synapses and nonexcitable glial cells that provide for homeostasis and defense. The evolution of neuroglia began with the emergence of the centralized nervous system and proceeded through a continuous increase in their complexity. In the primate brain, especially in the brain of humans, the astrocyte lineage is exceedingly complex, with the emergence of new types of astroglial cells possibly involved in interlayer communication and integration. [ABSTRACT FROM AUTHOR]

A personal narrative is presented which explores the author's experience of research work on synapses between dendrites.

The changes of synaptic ultrastructure were investigated by morphometry in the frontal (FC) and temporal (TC) cortex of adult and aged monkeys, to assess the potential role of age-related synaptic deterioration in neurodegeneration. The average synaptic size (S), the synaptic numeric density (Nv: number of synapses/μm3 of tissue), the synaptic surface density (Sv: overall area of synaptic junctional zones/μm3 of tissue), and the number of synapses/neuron (Syn/Neur) were calculated. In FC, significant differences of Nv and Sv due to age were not revealed, while the S value was significantly increased in the aged animals. In TC, Sv did not change in relation to age, whereas Nv was significantly decreased and S significantly increased in aged monkeys. A percent distribution of S showed that the fraction of enlarged synapses (>0.20 μm2) was higher in TC than in FC, regardless of the age of the animals (21.3% versus 16.9% in adult and 33.9% versus 26.0% in aged monkeys, respectively). In aged animals, Syn/Neur was not significantly decreased in TC and not significantly increased in FC (4.4%). The above morphometric parameters account for the ongoing rearrangements of synaptic ultrastructure, reacting to the environmental stimuli. Our findings provide evidence of an age-related decline of synaptic plasticity in the brain of aged monkeys that is statistically significant in TC. According to current literature data on synaptic structural dynamics, this decay may represent an early and subtle alteration able to trigger the development of senile plaques and neurodegenerative events. [ABSTRACT FROM AUTHOR]