Deficits in memory performance and cognitive functioning in aging humans are perhaps the most critical aspect of aging. In principle they are amenable to understanding at the neurobiological level. From a casual perusal of the human literature it is not at all clear that memory deficits in normal aged humans are all that great. I was greatly impressed when I read an article by Donald Hebb, a pioneering scientist in my own field of brain and learning. He wrote it in his 74th year and titled it "On Watching Myself Get Old" (Hebb, 1978). He first noticed signs of aging when he was 47. He had been reading a scientific paper and as he read the paper he decided that he really must make a note of an observation. As he turned the page he discovered just this note in his own handwriting. He had no memory of having read the paper or having made the note. He then realized that at the time he had been doing extensive research, teaching, writing, chairing a department, traveling a great deal—in fact, he was not suffering from a memory deficit; his memory system was simply overloaded. He cut back a bit on his activities and his memory returned to its "normal haphazard effectiveness."

IN this book Prof. F. A. Beach reviews the literature on the "Interrelationships between endocrine secretions and patterns of overt response" in vertebrates, the purpose of the book being "not the exposition of a thesis but the supplying of a body of facts and references". These are classified under the following chapter headings : courtship and mating ; reversal or bisexuality of mating behaviour ; ovi-position, parturition and parental behaviour ; migration ; generalized aggression ; social dominance or submission, and territory defence ; emotion ; conditioning and other types of learning ; general locomotor activity ; homeostasis, metabolism, metamorphosis and moulting ; morphologic structures employed in specific behaviour patterns ; the role of nervous stimulation ; developmental aspects ; major sources of variability ; and interpretations of hormonal effects. The bias of treatment in favour of sexual behaviour reflects, as the author correctly points out, the tendency of experimentalists to concentrate on those phenomena in which behavioural responses to hormonal stimulation are most evident and most specific.Hormones and BehaviorA Survey of Interrelationships between Endocrine Secretions and Patterns of Overt Response. By Prof. Frank A. Beach. Pp. xv+368. (New York : Paul B. Hoeber, Inc.; London : Hamish Hamilton, Ltd., 1948.) 6.56 dollars.

A dominant tradition in animal learning, and among many who study brain mechanisms of learning, has been the association of stimuli--the formation of S-R bonds. The association of ideas tradition in learning was expressed most starkly by Watson in his S-R theory of behavior. Physiological and neural mechanisms of motivation and emotion have been a particular province of physiological psychology since the 1930s. Experimental work on brain substrates of motivation and emotion began with the studies of J. P. Karplus and A. Kreidl on effects of stimulating the hypothalamus. A general characterization of motivation at the behavioral level has always presented difficulties. In infrahuman animals there appears to be a better index of central alerting or arousal than cortical EEG desynchrony--hippocampal theta--as recent work in Lindsley's lab has indicated very clearly. Indeed, a deficit in spatial memory has been demonstrated after disruption of theta through medial septal lesions.

Synaptogenix scientists have pioneered a regenerative therapeutic strategy designed to reduce (1.) a beta-oligomers and hyperphosphorylated tau, but importantly, (2.) also restores the AD – induced loss of synaptic networks and neurons. In pre-clinical studies (Sun and Alkon, TIPS, 2019), increased numbers of mature, mushroom spine synapses were measured with serial electron micrographs of the hippocampus with the rat spatial maze memory task, and were further significantly increased by the Bryostatin-induced activation of the PKC epsilon-BDNF cascade (Hongpaisan and Alkon, PNAS, 2007). Similarly, Bryostatin increased the numbers of mature synapses, normalized cognitive deficits, and prevented neuronal death in pre-clinical models of neurodegeneration including AD (p<.01, 2-tailed), stroke, Fragile X syndrome, and traumatic brain injury. Subsequently, compassionate use trials showed marked improvements in advanced AD patients (Nelson et al., JAD, 2017). Thereafter, an initial pilot (13 weeks, N=150) trial of Bryostatin to treat AD, Study #202, and a 2 nd (13 weeks, N=100) pilot trial, Study #203, included identical protocols: 7 i.v. doses of 20 mcg / kg Bryostatin over 11 weeks with Placebo groups in each. Bryostatin Treatment (at Week #13) in the 1 st trial improved Severe Impairment Battery (SIB) scores over baseline (+4.5 over baseline, p<.04, 2-tailed, pre-specified exploratory analyses of AD patients, MMSE 14 – 4, vs. placebo, without chronic Namenda, Farlow et al., J. Alz. Dis., 2019). In a second pilot trial, Bryostatin caused significant SIB improvement (+4.12 over baseline) in the pre-specified Moderate Stratum (MMSE 10 – 14) of advanced AD patients without Namenda (p < .005, 2-tailed). In both trials, trend analyses demonstrated increased drug benefit with increasing dosing number. In a pooled trend analysis of Studies #202, 203, Bryostatin caused highly significant benefit (p<.001) and Placebo was NS. While issues such as baseline imbalance (Study #203) and Namenda blockade of Bryostatin efficacy (Study #202) prevented reaching primary endpoints, these pre-specified exploratory analyses (see above) revealed clear evidence of Bryostatin therapeutic efficacy, now being tested in an NIH-sponsored, 6-month trial, incorporating lessons learned from these pilot studies. This potential efficacy involved significant improvement over baseline, not only reduction in the rate of cognitive decline.

This chapter begins with a brief review of the phenomena of habituation and sensitization, the current status of research on basic neurobiological mechanisms, and two theories: the model-comparator and the dual-process. It considers briefly the possible central underpinnings of "arousal" vis-a-vis orienting, and the relation of arousal to learning. Habituation appears to be the most ubiquitous form of behavioral plasticity. One of the parametric features of habituation, the "below-zero" effect, appears to have encountered difficulties recently in the context of habituation of various components of the human orienting reaction. Reflexes of the spinal mammal have been the most widely used as a model biological system for analysis of neural mechanisms underlying habituation and "dishabituation," or sensitization. A monosynaptic pathway in the isolated frog spinal cord has provided a useful model of habituation in the vertebrate central nervous system. The dual-process theory assumes that the mechanism of habituation is simply a decrease in synaptic transmission with repeated stimulation.

Bryostatin, pre-clinically shown to induce synaptogenesis and prevent neuronal death, is being evaluated in a double-blind, placebo-controlled confirmatory trial as a treatment for advanced Alzheimer's disease patients with a dose regimen of 20 μg of bryostatin compared to placebo. 108 subjects were randomized in a 1:1 treatment allocation. Subjects on Namenda (memantine) were excluded. Namenda was previously shown to block sustained cognitive improvement observed in a recently completed Phase II trial. (cf. Farlow et al., 2019 6 ). In the present confirmatory trial, each patient received two initial doses of study drug, bryostatin 20 μg or placebo, administered by infusions 1 week apart, followed by doses every 2 weeks; a total of 7 doses over 12 weeks. The primary endpoint is Severe Impairment Battery (SIB) score at 13 weeks versus placebo. (Analysis) In comparing 20 ug bryostatin with placebo using the SIB change from baseline as the endpoint, a study with a size of 50 patients per group would provide 84% power under alpha=0.05 to detect a 4.0 difference. The initial primary efficacy analysis will use ANCOVA tests with appropriate imputation methods to correct for patient drop-outs. Additional efficacy analyses will be done at weeks 5, 9 and 15. As a secondary analysis, patients in the Mini Mental State Exam, version 2 (MMSE-2) 4–9 and 10–15 stratification groups will be analyzed by group following the same methods used for the primary analysis. (Hypothesis)

Bryostatin, pre-clinically shown to induce synaptogenesis and prevent neuronal death, was evaluated via a double-blind, placebo-controlled trial with two doses (20 ug and 40 ug) of bryostatin compared to placebo. 150 subjects were randomized in a 1:1:1 treatment allocation. Each patient received initial doses 1 week apart, followed by every 2 weeks – for 11 weeks. The endpoints were severe impairment battery (SIB) scores at 0,5, 9, 13, and 15 weeks (30 days after the last dose). Because PKC epsilon, the target of bryostatin, controls NMDA function that is blocked by memantine, a pre-specified exploratory analysis of the treatment effect of Bryostatin for patients stratified by memantine usage, as a baseline therapy, was of particular interest. The initial primary efficacy analysis used a mixed model (MMRM) to handle missing data. However, since there were few missing observations for patients naïve to memantine, the complex MMRM modeling for analysis was not needed. Moreover, to avoid large potential intra-patient SIB variation over time, for the present analysis, we considered the change in average score collected during week 13-15 from baseline as the endpoint. The treatment effect estimate was based on the simple, transparent two-sample t-statistic for assessing the between-group-difference. In comparing 20 ug bryostatin with placebo for Memantine-naïve patients, the difference in SIB change from baseline was 6.1 points with 95% confidence interval of (1.5, 10.7) and p = 0.012, suggesting 20 ug bryostatin was highly significantly better than placebo. On the other hand, there was no treatment effect for memantine-dosed patients. Furthermore, with repeated measures of SIB over time for memantine-naïve patients, the 20ug bryostatin group showed early benefit starting at Week 5 and the positive trend was sustained for the entire study follow-up. The results of these new analyses are consistent with, although clearer than, previous analyses that indicated persistence of bryostatin benefit even 30 days after all dosing was completed. Bryostatin, without memantine, shows potential as a modifier of Alzheimer's disease – to be confirmed by additional studies.

Hippocampal pyramidal neurons exhibit a rapid within-trial increase in firing frequency during classical conditioning of the rabbit eyelid response. It has been pro- posed that the cellular mechanisms responsible for hippocam- pal long-term potentiation (LTP) may also mediate this learn- ing-dependent increase in neuronal activity. The induction of LTP in rat hippocampal slices results in an increase in the number of (3H)glutamate-binding sites in the potentiated re- gion. The present study investigates the kinetics of (3H)gluta- mate binding to hippocampal synaptic membranes after eyelid conditioning in the rabbit. We report that the regional distri- bution of (?H)glutamate binding across the layers of rabbit hippocampus is compatible with a dendritic localization. The pharmacological and ionic properties of the binding suggest that it is associated with an excitatory amino acid receptor. After eyelid conditioning, the maximal number of hippocam- pal (3H)glutamate-binding sites is increased in animals receiv- ing paired presentations of the tone conditioned stimulus and corneal air-puff unconditioned stimulus relative to that found in naive or unpaired control animals. These results strengthen the hypothesis that an LTP-like mechanism underlies the in- crease in hippocampal firing frequency during rabbit eyelid conditioning.

Karl Lashley was the most important and influential American Scientist in the first half of the twentieth century in the development of modern biological psychology. He was born in Davis, West Virginia on 7 June 1890 and died in Poitiers, France on 7 August 1958. He obtained his PhD at Johns Hopkins with H.S. Jennings and also worked with Adolf Meyer and John B. Watson. Lashley developed the lesion-behavioral methodology to analyze brain substrates of learning and memory, and revolutionized the field. His analysis of the problem of serial order in behavior was a precursor of modern cognitive neuroscience. His critical analysis of all extant theories of brain, learning, and behavior, including his own, was so compelling that none of these theories survived. On the other hand, he contributed an extremely important empirical literature on the role of the visual cortex in visual discriminations, on recovery of function following brain injury, on the organization of thalamocortical projection systems, and on cortical cytoarchitectonics. 'Eminent psychologist with no earned degree in psychology, famous theorist who specialized in disproving theories, including his own, inspiring teacher who described all teaching as useless'.

The hypothesis that anatomical or physiological factors can constrain the production of vocalizations is supported by an increasing number of examples from a range of taxa, where acoustic variation is related to sex, body‐size or condition. In this study, we combine anatomical and acoustic investigations in herring gulls Larus argentatus to 1) identify co‐variation between sex, body size and the dimensions of the vocal apparatus and 2) test the possible effect of this co‐variation on interindividual variation in the acoustics of alarm calls. We found that the vocal apparatus was sexually dimorphic, with males having longer trachea and bigger vibratile membranes than females. We also identified a relationship between the head–bill length – a secondary sexual trait – and the length of the trachea in males only. However, we failed to identify corresponding sex‐ and body‐size related variation in the acoustic components of alarm calls. We suggest that this absence of a relationship between anatomical and acoustic dimensions may reflect the lack of biomechanical constraints exerted during the production of alarm calls, and that such relationships are more likely to be expressed in this species’ sexual calls, whose production is characterised by more pronounced, ritualised postures that are more likely to highlight inter‐individual size variation.

We argue here that we have succeeded in localizing an essential memory trace for a basic form of associative learning and memory - classical conditioning of discrete responses learned with an aversive stimulus - to the anterior interpositus nucleus of the cerebellum. We first identified the entire essential circuit, using eyelid conditioning as the model system, and used reversible inactivation, during training, of critical structures and activation of pathways to localize definitively the essential memory trace. This discovery and the associated studies have: 1) shown that the essential cerebellar circuit applies equally to all mammals studied, including humans; 2) shown that this cerebellar circuit holds for the learning of any discrete behavioral response elicited by an aversive US, not just eyelid closure; 3) identified the essential circuit and process for reinforcement for this form of learning; 4) shown that this form of learning and its essential cerebellar circuitry is phylogenetically very old; 5) solved the long-standing puzzle of where memory traces are formed in the brain when the CS is electrical stimulation of the cerebral cortex in conditioning; 6) shown that this cerebellar circuitry forms the essential neural substrate for the behavioral phenomenon of "blocking", and hence, 7) provides the first clear neural instantiation of the Rescorla-Wagner learning algorithm; 8) shown that the fundamental neural process underlying this form of learning is a strengthening of preexisting pathways, and 9) shown that the basic mechanism underlying this strengthening is the formation of new excitatory synapses. This article is part of a Special Issue entitled SI: Brain and Memory.