On the role of theory and modeling in neuroscience

In recent years, the field of neuroscience has gone through rapid experimental advances and extensive use of quantitative and computational methods. This accelerating growth has created a need for methodological analysis of the role of theory and the modeling approaches currently used in this field. Toward that end, we start from the general view that the primary role of science is to solve empirical problems, and that it does so by developing theories that can account for phenomena within their domain of application. We propose a commonly-used set of terms - descriptive, mechanistic, and normative - as methodological designations that refer to the kind of problem a theory is intended to solve. Further, we find that models of each kind play distinct roles in defining and bridging the multiple levels of abstraction necessary to account for any neuroscientific phenomenon. We then discuss how models play an important role to connect theory and experiment, and note the importance of well-defined translation functions between them. Furthermore, we describe how models themselves can be used as a form of experiment to test and develop theories. This report is the summary of a discussion initiated at the conference Present and Future Theoretical Frameworks in Neuroscience, which we hope will contribute to a much-needed discussion in the neuroscientific community

Brains, maturation times, and parenting

Finch and Sapolsky propose that the slow development of human infants and their consequent long period of dependency on their parents have favored the evolution of genes that retard brain senescence, specifically recently evolved variants of the apolipoprotein E gene. We examine here the probable reasons why human maturation is so slow, and the influence of this slow development on parental dependence and patterns of survival. Large brains are expensive in terms of energy, anatomic complexity, and the time required to reach particular stages of postnatal maturation. We hypothesize that the maturational time costs arise from the fact that the brain is unique among the organs of the body in requiring a great deal of interaction with the environment (learning experience) to achieve adult competence, and thus that the brain serves as a rate-limiting factor governing the maturation of the entire body. Although the brain achieves its adult size at an earlier age than the other organs of the body, it does not become structurally and functionally mature until some point after sexual maturity [30]. The classical studies of developmental myelination by Flechsig [14], [15] indicate that the brain matures slowly in stepwise hierarchies proceeding, for example, from the thalamus to the primary cortical sensory areas to the higher cortical areas of the temporal, parietal, and frontal lobes. Quartz and Sejnowski [33] have proposed that the brain builds sequentially from one level to the next on the basis of experience, and thus larger brains may require more time to mature, in part because they have more levels. We have examined the time costs associated with enlarged brains by analyzing the relationships between average brain size and the average times required to reach various stages of postnatal maturation, such as the eruption of various classes of teeth and reproductive maturity, in different primate species. Because both brain and developmental timing variables are related to body mass, we have first extracted the statistical effect of mass for each variable and then compared the residual values related to brain weight and maturation times (Fig. 1). The near identity of the five maturation timing relationships as a function of relative brain size illustrate the consistent, clock-like nature of these relationships (Fig. 2). It is remarkable that the times required to attain each of these maturational stages, which range from events occurring in infancy to the threshold of adulthood, are so similarly influenced by relative brain size. However, although the absolute times required by humans to reach any particular stage of maturation are longer than for any other primate, humans actually mature somewhat faster than would be expected for a primate of our brain size. We will return to this interesting point later in our discussion

Brains, maturation times, and parenting

Finch and Sapolsky propose that the slow development of human infants and their consequent long period of dependency on their parents have favored the evolution of genes that retard brain senescence, specifically recently evolved variants of the apolipoprotein E gene. We examine here the probable reasons why human maturation is so slow, and the influence of this slow development on parental dependence and patterns of survival. Large brains are expensive in terms of energy, anatomic complexity, and the time required to reach particular stages of postnatal maturation. We hypothesize that the maturational time costs arise from the fact that the brain is unique among the organs of the body in requiring a great deal of interaction with the environment (learning experience) to achieve adult competence, and thus that the brain serves as a rate-limiting factor governing the maturation of the entire body. Although the brain achieves its adult size at an earlier age than the other organs of the body, it does not become structurally and functionally mature until some point after sexual maturity [30]. The classical studies of developmental myelination by Flechsig [14], [15] indicate that the brain matures slowly in stepwise hierarchies proceeding, for example, from the thalamus to the primary cortical sensory areas to the higher cortical areas of the temporal, parietal, and frontal lobes. Quartz and Sejnowski [33] have proposed that the brain builds sequentially from one level to the next on the basis of experience, and thus larger brains may require more time to mature, in part because they have more levels. We have examined the time costs associated with enlarged brains by analyzing the relationships between average brain size and the average times required to reach various stages of postnatal maturation, such as the eruption of various classes of teeth and reproductive maturity, in different primate species. Because both brain and developmental timing variables are related to body mass, we have first extracted the statistical effect of mass for each variable and then compared the residual values related to brain weight and maturation times (Fig. 1). The near identity of the five maturation timing relationships as a function of relative brain size illustrate the consistent, clock-like nature of these relationships (Fig. 2). It is remarkable that the times required to attain each of these maturational stages, which range from events occurring in infancy to the threshold of adulthood, are so similarly influenced by relative brain size. However, although the absolute times required by humans to reach any particular stage of maturation are longer than for any other primate, humans actually mature somewhat faster than would be expected for a primate of our brain size. We will return to this interesting point later in our discussion

Offset responses in the auditory cortex show unique history dependence.

Sensory responses typically vary depending on the recent history of sensory experience. This is essential for processes including adaptation, efficient coding, and change detection. In the auditory cortex (AC), the short-term history-dependence of sound-evoked (onset) responses has been well characterized. Yet many AC neurons also respond to sound terminations, and little is known about the history-dependence of these "offset" responses, whether the short-term dynamics of onset and offset responses are correlated, or how these properties are distributed among cell types. Here we presented awake male and female mice with repeating noise burst stimuli while recording single unit activity from primary AC. We identified PV and SST interneurons through optotagging, and also separated narrow-spiking from broad-spiking units. We found that offset responses are typically less depressive than onset responses, and this result was robust to a variety of stimulus parameters, controls, measurement types, and selection criteria. Whether a cell's onset response facilitates or depresses does not predict whether its offset response facilitates or depresses. Cell types differed in the dynamics of their onset responses, and in the prevalence but not the dynamics of their offset responses. Finally, we clustered cells according to spiking responses and found that response clusters were associated with cell type. Each cluster contained cells of several types, but even within a cluster, cells often showed cell type specific response dynamics. We conclude that onset and offset responses are differentially influenced by recent sound history, and discuss the implications of this for the encoding of ongoing sound stimuli.SIGNIFICANCE STATEMENT:Sensory neuron responses depend on stimulus history. This history dependence is crucial for sensory processing, is precisely controlled at individual synapses and circuits, and is adaptive to the specific requirements of different sensory systems. In the auditory cortex, neurons respond to sound cessation as well as to sound itself, but how history dependence is utilized along this separate, "offset" information stream is unknown. We show that offset responses are more facilitatory than sound responses, even in neurons where sound responses depress. In contrast to sound onset responses, offset responses are absent in many cells, are relatively homogenous, and show no cell-type specific differences in history dependence. Offset responses thus show unique response dynamics, suggesting their unique functions

Visual Information Present in Infragranular Layers of Mouse Auditory Cortex

The cerebral cortex is a major hub for the convergence and integration of signals from across the sensory modalities; sensory cortices, including primary regions, are no exception. Here we show that visual stimuli influence neural firing in the auditory cortex of awake male and female mice, using multisite probes to sample single units across multiple cortical layers. We demonstrate that visual stimuli influence firing in both primary and secondary auditory cortex. We then determine the laminar location of recording sites through electrode track tracing with fluorescent dye and optogenetic identification using layer-specific markers. Spiking responses to visual stimulation occur deep in auditory cortex and are particularly prominent in layer 6. Visual modulation of firing rate occurs more frequently at areas with secondary-like auditory responses than those with primary-like responses. Auditory cortical responses to drifting visual gratings are not orientation-tuned, unlike visual cortex responses. The deepest cortical layers thus appear to be an important locus for cross-modal integration in auditory cortex.SIGNIFICANCE STATEMENT The deepest layers of the auditory cortex are often considered its most enigmatic, possessing a wide range of cell morphologies and atypical sensory responses. Here we show that, in mouse auditory cortex, these layers represent a locus of cross-modal convergence, containing many units responsive to visual stimuli. Our results suggest that this visual signal conveys the presence and timing of a stimulus rather than specifics about that stimulus, such as its orientation. These results shed light on both how and what types of cross-modal information is integrated at the earliest stages of sensory cortical processing

Visual Information Present in Infragranular Layers of Mouse Auditory Cortex

The cerebral cortex is a major hub for the convergence and integration of signals from across the sensory modalities; sensory cortices, including primary regions, are no exception. Here we show that visual stimuli influence neural firing in the auditory cortex of awake male and female mice, using multisite probes to sample single units across multiple cortical layers. We demonstrate that visual stimuli influence firing in both primary and secondary auditory cortex. We then determine the laminar location of recording sites through electrode track tracing with fluorescent dye and optogenetic identification using layer-specific markers. Spiking responses to visual stimulation occur deep in auditory cortex and are particularly prominent in layer 6. Visual modulation of firing rate occurs more frequently at areas with secondary-like auditory responses than those with primary-like responses. Auditory cortical responses to drifting visual gratings are not orientation-tuned, unlike visual cortex responses. The deepest cortical layers thus appear to be an important locus for cross-modal integration in auditory cortex.SIGNIFICANCE STATEMENT The deepest layers of the auditory cortex are often considered its most enigmatic, possessing a wide range of cell morphologies and atypical sensory responses. Here we show that, in mouse auditory cortex, these layers represent a locus of cross-modal convergence, containing many units responsive to visual stimuli. Our results suggest that this visual signal conveys the presence and timing of a stimulus rather than specifics about that stimulus, such as its orientation. These results shed light on both how and what types of cross-modal information is integrated at the earliest stages of sensory cortical processing

Parenting and survival in anthropoid primates: Caretakers live longer

Most anthropoid primates are slow to develop, their offspring are mostly single births, and the interbirth intervals are long. To maintain a stable population, parents must live long enough to sustain the serial production of a sufficient number of young to replace themselves while allowing for the death of offspring before they can reproduce. However, in many species there is a large differential between the sexes in the care provided to offspring. Therefore, we hypothesize that in slowly developing species with single births, the sex that bears the greater burden in the care of offspring will tend to survive longer. Males are incapable of gestating infants and lactating, but in several species fathers carry their offspring for long periods. We predict that females tend to live longer than males in the species where the mother does most or all of the care of offspring, that there is no difference in survival between the sexes in species in which both parents participate about equally in infant care, and that in the species where the father does a greater amount of care than the mother, males tend to live longer. The hypothesis is supported by survival data for males and females in anthropoid primate species

Cortical Interneurons Differentially Regulate the Effects of Acoustic Context

Both behavioral and neural responses to sounds are generally modified by the acoustic context in which they are encountered. As an example, in the auditory cortex, preceding sounds can powerfully suppress responses to later, spectrally similar sounds—a phenomenon called forward suppression (FWS). Whether cortical inhibitory networks shape such suppression or whether it is wholly regulated by common mechanisms such as synaptic depression or spike frequency adaptation is controversial. Here, we show that optogenetically suppressing somatostatin-positive (Sst+) interneurons weakens forward suppression, often revealing facilitation in neurons that are normally forward-suppressed. In contrast, inactivating parvalbumin-positive (Pvalb+) interneurons strengthens forward suppression and alters its frequency dependence. In a simple network model, we show that these effects can be accounted for by differences in short-term synaptic dynamics of inputs onto Pvalb+ and Sst+ interneurons. These results demonstrate separate roles for somatostatin and parvalbumin interneurons in regulating the context dependence of auditory processing

Cortical Interneurons Differentially Regulate the Effects of Acoustic Context

Both behavioral and neural responses to sounds are generally modified by the acoustic context in which they are encountered. As an example, in the auditory cortex, preceding sounds can powerfully suppress responses to later, spectrally similar sounds—a phenomenon called forward suppression (FWS). Whether cortical inhibitory networks shape such suppression or whether it is wholly regulated by common mechanisms such as synaptic depression or spike frequency adaptation is controversial. Here, we show that optogenetically suppressing somatostatin-positive (Sst+) interneurons weakens forward suppression, often revealing facilitation in neurons that are normally forward-suppressed. In contrast, inactivating parvalbumin-positive (Pvalb+) interneurons strengthens forward suppression and alters its frequency dependence. In a simple network model, we show that these effects can be accounted for by differences in short-term synaptic dynamics of inputs onto Pvalb+ and Sst+ interneurons. These results demonstrate separate roles for somatostatin and parvalbumin interneurons in regulating the context dependence of auditory processing